Novel ptefb inhibiting macrocyclic compounds

ABSTRACT

The present invention relates to novel modified macrocyclic compounds with improved tolerability of general formula (I) as described and defined herein, and methods for their preparation, their use for the treatment and/or prophylaxis of disorders, in particular of hyper-proliferative disorders and/or virally induced infectious diseases and/or of cardiovascular diseases. The invention further relates to intermediate compounds useful in the preparation of said compounds of general formula (I).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.16/498,662, filed on Sep. 27, 2019, which is a U.S. National StageApplication under 35 U.S.C. § 371 of International Application No.PCT/EP2018/057359, filed internationally on Mar. 22, 2018, which claimsbenefit of priority to European Application No. 17193837.6, filed Sep.28, 2017 and European Application No. 17163377.9, filed Mar. 28, 2017,all of which are incorporated by reference herein in their entireties.

The present invention relates to novel modified macrocyclic compounds ofgeneral formula (I) as described and defined herein, and methods fortheir preparation, their use for the treatment and/or prophylaxis ofdisorders, in particular of hyper-proliferative disorders and/or virallyinduced infectious diseases and/or of cardiovascular diseases. Theinvention further relates to intermediate compounds useful in thepreparation of said compounds of general formula (I).

The family of cyclin-dependent kinase (CDK) proteins consists of membersthat are key regulators of the cell division cycle (cell cycle CDK's),that are involved in regulation of gene transcription (transcriptionalCDK's), and of members with other functions. CDKs require for activationthe association with a regulatory cyclin subunit. The cell cycle CDKsCDK1/cyclin B, CDK2/cyclin A, CDK2/cyclinE, CDK4/cyclinD, andCDK6/cyclinD get activated in a sequential order to drive a cell intoand through the cell division cycle. The transcriptional CDKsCDK9/cyclin T and CDK7/cyclin H regulate the activity of RNApolymeraseII via phosphorylation of the carboxy-terminal domain (CTD). Positivetranscription factor b (PTEFb) is a heterodimer of CDK9 and one of thecyclin partners cyclin T1, cyclin T2a or T2b.

Whereas CDK9 (NCBI GenBank Gene ID 1025) is exclusively involved intranscriptional regulation, CDK7 in addition participates in cell cycleregulation as CDK-activating kinase (CAK). Transcription of genes by RNApolymerase II is initiated by assembly of the pre-initiation complex atthe promoter region and phosphorylation of Ser 5 and Ser 7 of the CTD byCDK7/cyclin H. For a major fraction of genes RNA polymerase II stopsmRNA transcription after it moved 20-40 nucleotides along the DNAtemplate. This promoter-proximal pausing of RNA polymerase II ismediated by negative elongation factors and is recognized as a majorcontrol mechanism to regulate expression of rapidly induced genes inresponse to a variety of stimuli (Cho et al., Cell Cycle 9, 1697, 2010).PTEFb is crucially involved in overcoming promoter-proximal pausing ofRNA polymerase II and transition into a productive elongation state byphosphorylation of Ser 2 of the CTD as well as by phosphorylation andinactivation of negative elongation factors (reviewed in Jonkers andJohn, Nat. Rev. Mol. Cell Biol. 16, 167, 2015).

Activity of PTEFb itself is regulated by several mechanisms. About halfof cellular PTEFb exists in an inactive complex with 7SK small nuclearRNA (7SK snRNA), La-related protein 7 (LARP7/PIP7S) and hexamethylenebis-acetamide inducible proteins 1/2 (HEXIM1/2, He et al., Mol Cell 29,588, 2008). The remaining half of PTEFb exists in an active complexcontaining the bromodomain protein Brd4 (Yang et al., Mol Cell 19, 535,2005). Brd4 recruits PTEFb through interaction with acetylated histonesto chromatin areas primed for gene transcription. Through alternatelyinteracting with its positive and negative regulators, PTEFb ismaintained in a functional equilibrium: PTEFb bound to the 7SK snRNAcomplex represents a reservoir from which active PTEFb can be releasedon demand of cellular transcription and cell proliferation (Zhou & Yik,Microbiol Mol Biol Rev 70, 646, 2006). Furthermore, the activity ofPTEFb is regulated by posttranslational modifications includingphosphorylation/de-phosphorylation, ubiquitination, and acetylation(reviewed in Cho et al., Cell Cycle 9, 1697, 2010).

Deregulated activity of CDK9 kinase activity of the PTEFb heterodimer isassociated with a variety of human pathological settings such ashyper-proliferative diseases (e.g. cancer), virally induced infectiousdiseases or cardiovascular diseases:

Cancer is regarded as a hyper-proliferative disorder mediated by adisbalance of proliferation and cell death (apoptosis). High levels ofanti-apoptotic Bcl-2-family proteins are found in various human tumorsand account for prolonged survival of tumor cells and therapyresistance. Inhibition of PTEFb kinase activity was shown to reducetranscriptional activity of RNA polymerase II leading to a decline ofshort-lived anti-apoptotic proteins, especially Mcl-1 and XIAP,reinstalling the ability of tumor cells to undergo apoptosis. A numberof other proteins associated with the transformed tumor phenotype (suchas Myc, NF-kB responsive gene transcripts, mitotic kinases) are eithershort-lived proteins or are encoded by short-lived transcripts which aresensitive to reduced RNA polymerase II activity mediated by PTEFbinhibition (reviewed in Wang & Fischer, Trends Pharmacol Sci 29, 302,2008).

Many viruses rely on the transcriptional machinery of the host cell forthe transcription of their own genome. In case of HIV-1, RNA polymeraseII gets recruited to the promoter region within the viral LTR's. Theviral transcription activator (Tat) protein binds to nascent viraltranscripts and overcomes promoter-proximal RNA polymerase II pausing byrecruitment of PTEFb which in turn promotes transcriptional elongation.Furthermore, the Tat protein increases the fraction of active PTEFb byreplacement of the PTEFb inhibitory proteins HEXIM1/2 within the 7SKsnRNA complex. Recent data have shown that inhibition of the kinaseactivity of PTEFb is sufficient to block HIV-1 replication at kinaseinhibitor concentrations that are not cytotoxic to the host cells(reviewed in Wang & Fischer, Trends Pharmacol Sci 29, 302, 2008).Similarly, recruitment of PTEFb by viral proteins has been reported forother viruses such as B-cell cancer-associated Epstein-Barr virus, wherethe nuclear antigen EBNA2 protein interacts with PTEFb (Bark-Jones etal., Oncogene, 25, 1775, 2006), and the human T-lymphotropic virus type1 (HTLV-1), where the transcriptional activator Tax recruits PTEFb (Zhouet al., J Virol. 80, 4781, 2006).

Cardiac hypertrophy, the heart's adaptive response to mechanicaloverload and pressure (hemodynamic stress e.g. hypertension, myocardialinfarction), can lead, on a long term, to heart failure and death.Cardiac hypertrophy was shown to be associated with increasedtranscriptional activity and RNA polymerase II CTD phosphorylation incardiac muscle cells. PTEFb was found to be activated by dissociationfrom the inactive 7SK snRNA/HEXIM1/2 complex. These findings suggestpharmacological inhibition of PTEFb kinase activity as a therapeuticapproach to treat cardiac hypertrophy (reviewed in Dey et al., CellCycle 6, 1856, 2007).

In summary, multiple lines of evidence suggest that selective inhibitionof the CDK9 kinase activity of the PTEFb heterodimer (=CDK9 and one ofthe cyclin partners cyclin T1, cyclin T2a or T2b) represents aninnovative approach for the treatment of diseases such as cancer, viraldiseases, and/or diseases of the heart. CDK9 belongs to a family of atleast 13 closely related kinases of which the subgroup of the cell cycleCDK's fulfills multiple roles in regulation of cell proliferation. Thus,co-inhibition of cell cycle CDKs (e.g. CDK1/cyclin B, CDK2/cyclin A,CDK2/cyclinE, CDK4/cyclinD, CDK6/cyclinD) and of CDK9, is expected toimpact normal proliferating tissues such as intestinal mucosa, lymphaticand hematopoietic organs, and reproductive organs. To maximize thetherapeutic value of CDK9 kinase inhibitors, molecules with improvedduration of action and/or high potency and efficacy and/or selectivitytowards CDK9 are required.

CDK inhibitors in general as well as CDK9 inhibitors are described in anumber of different publications: WO2008129070 and WO2008129071 bothdescribe 2,4 disubstituted aminopyrimidines as CDK inhibitors ingeneral. It is also asserted that some of these compounds may act asselective CDK9 inhibitors (WO2008129070) and as CDK5 inhibitors(WO2008129071), respectively, but no specific CDK9 IC₅₀ (WO2008129070)or CDK5 IC₅₀ (WO2008129071) data are presented. These compounds do notcontain a fluorine atom in 5-position of the pyrimidine core.

WO2008129080 discloses 4,6 disubstituted aminopyrimidines anddemonstrates that these compounds show an inhibitory effect on theprotein kinase activity of various protein kinases, such as CDK1, CDK2,CDK4, CDK5, CDK6 and CDK9, with a preference for CDK9 inhibition(example 80).

WO2005026129 discloses 4,6 disubstituted aminopyrimidines anddemonstrates that these compounds show an inhibitory effect on theprotein kinase activity of various protein kinases, in particular CDK2,CDK4, and CDK9.

WO2009118567 discloses pyrimidine and [1,3,5]triazine derivatives asprotein kinase inhibitors, in particular CDK2, CDK7 and CDK9.

WO2011116951 discloses substituted triazine derivatives as selectiveCDK9 inhibitors.

WO2012117048 discloses disubstituted triazine derivatives as selectiveCDK9 inhibitors.

WO2012117059 discloses disubstituted pyridine derivatives as selectiveCDK9 inhibitors.

WO2012143399 discloses substituted4-aryl-N-phenyl-1,3,5-triazin-2-amines as selective CDK9 inhibitors.

EP1218360 B1, which corresponds to US2004116388A1, U.S. Pat. No.7,074,789B2 and WO2001025220A1, describes triazine derivatives as kinaseinhibitors, but does not disclose potent or selective CDK9 inhibitors.

WO2008079933 discloses aminopyridine and aminopyrimidine derivatives andtheir use as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 or CDK9inhibitors.

WO2011012661 describes aminopyridine derivatives useful as CDKinhibitors.

WO2011026917 discloses carboxamides derived from substituted4-phenylpyridine-2-amines as inhibitors of CDK9.

WO2012066065 discloses phenyl-heteroaryl amines as inhibitors of CDK9. Aselectivity towards CDK9 over other CDK isoforms is preferred, howeverdisclosure of CDK-inhibition data is confined to CDK 9. No bicyclic ringsystems are disclosed attached to the C4 position of the pyrimidinecore. Within the group attached to C4 of the pyrimidine core, alkoxyphenyls can be regarded as encompassed, but there is no suggestion for aspecific substitution pattern characterised by a fluorine atom attachedto C5 of the pyrimidine ring, and an aniline at C2 of the pyrimidine,featuring a substituted sulfonyl-methylene group in meta position.Compounds shown in the examples typically feature a substitutedcycloalkyl group as R¹ but no phenyl.

WO2012066070 discloses 3-(aminoaryl)-pyridine compounds as inhibitors ofCDK9. The biaryl core mandatorily consists of two heteroaromatic rings.

WO2012101062 discloses substituted bi-heteroaryl compounds featuring a2-aminopyridine core as inhibitors of CDK9. The biaryl core mandatorilyconsists of two heteroaromatic rings.

WO2012101063 discloses carboxamides derived from substituted4-(heteroaryl)-pyridine-2-amines as inhibitors of CDK9.

WO2012101064 discloses N-acyl pyrimidine biaryl compounds as inhibitorsof CDK9.

WO2012101065 discloses pyrimidine biaryl compounds as inhibitors ofCDK9. The biaryl core mandatorily consists of two heteroaromatic rings.

WO2012101066 discloses pyrimidine biaryl compounds as inhibitors ofCDK9. Substitution R¹ of the amino group attached to the heteroaromaticcore is confined to non-aromatic groups but does not cover substitutedphenyls. Furthermore, the biaryl core mandatorily consists of twoheteroaromatic rings.

WO2011077171 discloses 4,6-disubstituted aminopyrimidine derivatives asinhibitors of CDK9.

WO2014031937 discloses 4,6-disubstituted aminopyrimidine derivatives asinhibitors of CDK9.

WO2013037896 discloses disubstituted 5-fluoropyrimidines as selectiveinhibitors of CDK9.

WO2013037894 discloses disubstituted 5-fluoropyrimidine derivativescontaining a sulfoximine group as selective inhibitors of CDK9.

Wang et al. (Chemistry & Biology 17, 1111-1121, 2010) describe2-anilino-4-(thiazol-5-yl)pyrimidine transcriptional CDK inhibitors,which show anticancer activity in animal models.

WO2014060376 discloses substituted4-(ortho)-fluorophenyl-5-fluoropyrimidin-2-yl amine derivativescontaining a sulfone group as selective inhibitors of CDK9.

WO2014060375 discloses substituted5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivatives containing asulfone group as selective inhibitors of CDK9.

WO2014060493 discloses substituted N-(pyridin-2-yl)pyrimidin-4-aminederivatives containing a sulfone group as selective inhibitors of CDK9.

WO2014076028 discloses substituted4-(ortho)-fluorophenyl-5-fluoropyrimidin-2-yl amine derivativescontaining a sulfoximine group as selective inhibitors of CDK9.

WO2014076091 discloses substituted5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivatives containing asulfoximine group as selective inhibitors of CDK9.

WO2014076111 discloses substituted N-(pyridin-2-yl)pyrimidin-4-aminederivatives containing a sulfoximine group as selective inhibitors ofCDK9.

WO2015001021 discloses 5-fluoro-N-(pyridin-2-yl)pyridin-2-aminederivatives containing a sulfoximine group as selective inhibitors ofCDK9.

WO 2015136028 discloses 5-fluoro-N-(pyridin-2-yl)pyridin-2-aminederivatives containing a sulfone group as selective inhibitors of CDK9.

WO2004009562 discloses substituted triazine kinase inhibitors. Forselected compounds CDK1 and CDK4 test data, but no CDK9 data ispresented.

WO2004072063 describes heteroaryl (pyrimidine, triazine) substitutedpyrroles as inhibitors of protein kinases such as ERK2, GSK3, PKA orCDK2.

WO2010009155 discloses triazine and pyrimidine derivatives as inhibitorsof histone deacetylase and/or cyclin dependent kinases (CDKs). Forselected compounds CDK2 test data is described.

WO2003037346 (corresponding to U.S. Pat. No. 7,618,968B2, U.S. Pat. No.7,291,616B2, US2008064700A1, US2003153570A1) relates to aryl triazinesand uses thereof, including to inhibit lysophosphatidic acidacyltransferase beta (LPAAT-beta) activity and/or proliferation of cellssuch as tumor cells.

WO2005037800 discloses sulfoximine substituted anilino-pyrimidines asinhibitors of VEGFR and CDK kinases, in particular VEGFR2, CDK1 andCDK2, having no aromatic ring directly bonded to the pyrimidine ring andhaving the sulfoximine group directly bonded to the aniline group. NoCDK9 data are disclosed.

WO2008025556 describes carbamoyl sulfoximides having a pyrimidine core,which are useful as kinase inhibitors. No CDK9 data is presented. Nomolecules are exemplified, which possess a fluoropyrimidine core.

WO2002066481 describes pyrimidine derivatives as cyclin dependent kinaseinhibitors. CDK9 is not mentioned and no CDK9 data is presented.

WO2008109943 concerns phenyl aminopyri(mi)dine compounds and their useas kinase inhibitors, in particular as JAK2 kinase inhibitors. Thespecific examples mainly focus on compounds having a pyrimidine core.

WO2009032861 describes substituted pyrimidinyl amines as JNK kinaseinhibitors. The specific examples mainly focus on compounds having apyrimidine core.

WO2011046970 concerns amino-pyrimidine compounds as inhibitors of TBK1and/or IKK epsilon. The specific examples mainly focus on compoundshaving a pyrimidine core.

WO2012142329 concerns amino-pyrimidine compounds as inhibitors of TBK1and/or IKK epsilon.

WO2012139499 discloses urea substituted anilino-pyrimidines asinhibitors of various protein kinases.

WO2014106762 discloses 4-pyrimidinylamino-benzenesulfonamide derivativesas inhibitors of polo-like kinase-1.

Macrocyclic compounds have been described as therapeutically usefulsubstances, in particular of various protein kinases including cyclindependent kinases. However, the documents listed below do not disclosespecific compounds as inhibitors of CDK9.

WO2007147574 discloses sulfonamido-macrocycles as inhibitors of Tie2showing selectivity over CDK2 and Aurora kinase C, inter alia for thetreatment of diseases accompanied with dysregulated vascular growth.

WO2007147575 discloses further sulfonamido-macrocycles as inhibitors ofTie2 and KDR showing selectivity over CDK2 and Plk1, inter alia for thetreatment of diseases accompanied with dysregulated vascular growth.

WO2006066957/EP1674470 discloses further sulfonamido-macrocycles asinhibitors of Tie2 showing low cytotoxicity, inter alia for thetreatment of diseases accompanied with dysregulated vascular growth.

WO2006066956/EP1674469 discloses further sulfonamido-macrocycles asinhibitors of Tie2 showing low cytotoxicity, inter alia for thetreatment of diseases accompanied with dysregulated vascular growth.

WO2004026881/DE10239042 discloses macrocyclic pyrimidine derivatives asinhibitors of cyclin dependent kinases, in particular CDK1 and CDK2, aswell as VEGF-R, inter alia for the treatment of cancer. The compounds ofthe present invention differ from those disclosed in WO2004026881 infeaturing a mandatory biaromatic portion within the macrocyclic ringsystem. Furthermore, none of the example compounds disclosed inWO2004026881 features a group —CH₂-A-R¹, in which A and R¹ are asdefined for the compounds of the formula (I) of the present invention,attached to one of the two aromatic portions of the macrocyclic ringsystem.

WO2007079982/EP1803723 discloses macrocyclic benzenacyclononaphanes asinhibtors of multiple protein kinases, e.g. Aurora kinases A and C,CDK1, CDK2 and c-Kit, inter alia for the treatment of cancer. Thecompounds of the present invention differ from those disclosed in WO2007079982 in featuring a mandatory biaromatic portion within themacrocyclic ring system. Furthermore, the compounds of the presentinvention do not feature a group —S(═O)(N═R²)R¹ directly attached to thephenylene portion of the macrocyclic ring system as disclosed in WO2007079982.

WO2006106895/EP1710246 discloses sulfoximine-macrocycle compounds asinhibitors of Tie2 showing low cytotoxicity, inter alia for thetreatment of diseases accompanied with dysregulated vascular growth.

WO2012009309 discloses macrocyclic compounds fused to benzene andpyridine rings for the reduction of beta-amyloid production.

WO2009132202 discloses macrocyclic compounds as inhibitors of JAK 1, 2and 3, TYK2 and ALK and their use in the treatment of JAK/ALK-associateddiseases, including inflammatory and autoimmune disease as well ascancer.

WO2004078682/U.S. Pat. No. 7,151,096 discloses a class of cycliccompounds for treating or preventing diseases and disorders associatedwith cyclin-dependent kinases (CDKs) activity, particularly diseasesassociated with the activity of CDK2 and CDK5.

WO2015155197 discloses macrocyclic compounds as selective inhibitors ofCDK9 for the treatment and/or prophylaxis of disorders, in particular ofhyper-proliferative disorders and/or virally induced infectious diseasesand/or of cardiovascular diseases. The compounds of the presentinvention differ from those in WO2015155197 by the point of attachmentof bridging alkylenedioxy moiety.

WO2015150555 and WO2015150557 disclose substituted macrocylic compoundshaving EF2K inhibitory activity and optionally also Vps34 inhibitoryactivity. The compounds of the present invention differ from those inWO2015150555 and WO2015150557 i.a. by the point of attachment of thebridging moiety.

WO2008140420 discloses macrocylic compounds that may be useful as agentstargeting kinase related disorders. The compounds of the presentinvention differ from those in WO2008140420 i.a. by the structure of thebridging moiety.

ChemMedChem 2007, 2(1), 63-77 describes macrocyclic aminopyrimidines asmultitarget CDK and VEGF-R inhibitors with potent antiproliferativeactivity. The compounds of the present invention differ from thosedisclosed in said journal publication in featuring a mandatorybiaromatic portion within the macrocyclic ring system. Furthermore, noneof the compounds disclosed in ChemMedChem 2007, 2(1), 63-77 features agroup —CH₂-A-R¹ in which A and R¹ are as defined for the compounds ofthe formula (I) or the present invention, attached to one of the twoaromatic portions of the macrocyclic ring system.

Despite the fact that various inhibitors of CDKs are known, thereremains a need for selective CDK9 inhibitors, especially CDK9 inhibitorswhich are selective at high ATP concentrations, to be used for thetreatment of diseases such as hyper-proliferative diseases, viraldiseases, and/or diseases of the heart, which offer one or moreadvantages over the compounds known from prior art, such as:

-   -   improved activity and/or efficacy, allowing e.g. a dose        reduction    -   improved side effect profile, such as fewer undesired side        effects, lower intensity of side effects, or reduced        (cyto)toxicity    -   improved duration of action, e.g. by improved pharmacokinetics        and/or improved target residence time    -   Specifically modified PK profile to reduce unwanted side effects

A particular object of the invention is to provide selective CDK9 kinaseinhibitors, which show a high anti-proliferative activity in tumor celllines, such as HeLa, HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2, B16F10,A2780 or MOLM-13, compared to compounds known from prior art.

Another particular object of the invention is to provide selective CDK9kinase inhibitors which show an increased potency to inhibit CDK9activity at high ATP concentrations compared to compounds known fromprior art.

Another particular object of the invention is to provide selective CDK9kinase inhibitors which show an increased target residence time comparedto compounds known from prior art.

Another particular object of the invention is to provide selective CDK9kinase inhibitors which show an improved duration of action, e.g. byimproved pharmacokinetics and/or improved target residence time.

Further, it is an object of the present invention to provide selectiveCDK9 kinase inhibitors, which, compared to the compounds known fromprior art, show a high anti-proliferative activity in tumor cell lines,such as HeLa, HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2, B16F10, A2780 orMOLM-13, and/or which show an increased potency to inhibit CDK9 activity(demonstrated by a lower IC₅₀ value for CDK9/Cyclin T1), especially anincreased potency to inhibit CDK9 activity at high ATP concentrations,and/or which show an increased target residence time compared to thecompounds known from prior art.

Another particular object of the invention is to provide selective CDK9kinase inhibitors which show an improved therapeutic window.

A further object of the invention is to provide CDK9 kinase inhibitorssimultaneously featuring selectivity for CDK9/Cyclin T1 over CDK2/CyclinE, especially at high ATP concentrations.

The present invention relates to compounds of general formula (I)

wherein

-   A represents a bivalent moiety selected from the group consisting of    —S—, —S(═O)—, —S(═O)₂—, —S(═O)(═NR⁵)—; —S(═NR⁶)(═NR⁷)—;-   Z represents a hydrogen atom or a fluorine atom;-   L represents a C₃-C₈-alkylene moiety,    -   wherein said moiety is optionally substituted with    -   (i) one substituent selected from hydroxy, —NR⁸R⁹,        C₂-C₃-alkenyl-, C₂-C₃-alkynyl-, C₃-C₄-cycloalkyl-,        hydroxy-C₁-C₃-alkyl, —(CH₂)NR⁸R⁹, and/or    -   (ii) one or two or three or four substituents, identically or        differently, selected from halogen and C₁-C₃-alkyl-,    -   or wherein    -   one carbon atom of said C₃-C₈-alkylene moiety forms a three- or        four-membered ring together with a bivalent moiety to which it        is attached, wherein said bivalent moiety is selected from        —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂OCH₂—;-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a group selected from C₁-C₆-alkyl-, C₃-C₆-alkenyl-,    C₃-C₇-cycloalkyl-, heterocyclyl-, wherein said group is optionally    substituted with one or two or three substituents, identically or    differently, selected from the group consisting of hydroxy, cyano,    halogen, C₁-C₆-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₆-alkoxy-,    C₁-C₃-fluoroalkoxy-, —NH₂, alkylamino-, dialkylamino-, acetylamino-,    N-methyl-N-acetylamino-, cyclic amines, —OP(═O)(OH)₂, —C(═O)OH,    —C(═O)NH₂;-   R² represents a group selected from a hydrogen atom, a fluorine    atom, a chlorine atom, a bromine atom, cyano, C₁-C₃-alkyl-,    C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;-   R³, R⁴ represent, independently from each other, a group selected    from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine    atom, cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-,    C₁-C₃-fluoroalkoxy-;-   R⁵ represents a group selected from a hydrogen atom, cyano,    —C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O₂) R¹⁰, —C(═O)NR⁸R⁹, C₁-C₆-alkyl-,    C₃-C₇-cycloalkyl-, heterocyclyl-,    -   wherein said C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-        group is optionally substituted with one, two or three        substituents, identically or differently, selected from the        group consisting of halogen, hydroxy, cyano, C₁-C₃-alkyl-,        C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-;-   R⁶, R⁷ represents, independently from each other, a group selected    from a hydrogen atom, cyano, —C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O)₂R¹⁰,    —C(═O)NR⁸R⁹, C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-,    -   wherein said C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-        group is optionally substituted with one, two or three        substituents, identically or differently, selected from the        group consisting of halogen, hydroxy, cyano, C₁-C₃-alkyl-,        C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-;-   R⁸, R⁹ represent, independently from each other, a group selected    from a hydrogen atom, C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-,    heterocyclyl-, phenyl-, benzyl- and heteroaryl-,    -   wherein said C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-,        phenyl-, benzyl- or heteroaryl- group is optionally substituted        with one, two or three substituents, identically or differently,        selected from the group consisting of halogen, hydroxy,        C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-,        acetylamino-, N-methyl-N-acetylamino-, cyclic amines,        halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, or-   R⁸ and R⁹, together with the nitrogen atom they are attached to,    form a cyclic amine;    -   R¹⁰ represents a group selected from C₁-C₆-alkyl-,        halo-C₁-C₃-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl-,        benzyl- and heteroaryl-,    -   wherein said group is optionally substituted with one, two or        three substituents, identically or differently, selected from        the group consisting of halogen, hydroxy, C₁-C₃-alkyl-,        C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-,        or the enantiomers, diastereomers, salts, solvates or salts of        solvates thereof.

Compounds according to the invention are the compounds of the formula(I) and the salts, solvates and solvates of the salts thereof, thecompounds of the hereinafter recited formula which are encompassed byformula (I) and the salts, solvates and solvates of the salts thereof,and the compounds which are encompassed by formula (I) and are mentionedhereinafter as exemplary embodiments and the salts, solvates andsolvates of the salts thereof, where the compounds which are encompassedby formula (I) and are mentioned hereinafter are not already salts,solvates and solvates of the salts.

The compounds according to the invention may, depending on theirstructure, exist in stereoisomeric forms (enantiomers, diastereomers).The invention therefore relates to the enantiomers or diastereomers andrespective mixtures thereof. The stereoisomerically pure constituentscan be isolated in a known manner from such mixtures of enantiomersand/or diastereomers.

If the compounds according to the invention can be in tautomeric forms,the present invention encompasses all tautomeric forms.

Further, the compounds of the present invention can exist in free form,e.g. as a free base, or as a free acid, or as a zwitterion, or can existin the form of a salt. Said salt may be any salt, either an organic orinorganic addition salt, particularly any physiologically acceptableorganic or inorganic addition salt, customarily used in pharmacy.

Salts which are preferred for the purposes of the present invention arephysiologically acceptable salts of the compounds according to theinvention. However, salts which are not suitable for pharmaceuticalapplications per se, but which, for example, can be used for theisolation or purification of the compounds according to the invention,are also comprised.

The term “physiologically acceptable salt” refers to a relativelynon-toxic, inorganic or organic acid addition salt of a compound of thepresent invention, for example, see S. M. Berge, et al. “PharmaceuticalSalts,” J. Pharm. Sci. 1977, 66, 1-19.

Physiologically acceptable salts of the compounds according to theinvention encompass acid addition salts of mineral acids, carboxylicacids and sulfonic acids, for example salts of hydrochloric acid,hydrobromic acid, hydroiodic, sulfuric acid, bisulfuric acid, phosphoricacid, nitric acid or with an organic acid, such as formic, acetic,acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic,heptanoic, undecanoic, lauric, benzoic, salicylic,2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic,2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic,dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic,methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic,camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic,malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic,mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic,sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.

Physiologically acceptable salts of the compounds according to theinvention also comprise salts of conventional bases, such as, by way ofexample and by preference, alkali metal salts (for example sodium andpotassium salts), alkaline earth metal salts (for example calcium andmagnesium salts) and ammonium salts derived from ammonia or organicamines with 1 to 16 C atoms, such as, by way of example and bypreference, ethylamine, diethylamine, triethylamine,ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine,N-methylpiperidine, N-methylglucamine, dimethylglucamine,ethylglucamine, 1,6-hexadiamine, glucosamine, sarcosine, serinol,tris(hydroxymethyl)aminomethane, aminopropanediol, Sovak base, and1-amino-2,3,4-butanetriol. Additionally, the compounds according to theinvention may form salts with a quarternary ammonium ion obtainable e.g.by quarternisation of a basic nitrogen containing group with agents suchas lower alkylhalides such as methyl-, ethyl-, propyl-, andbutylchlorides, -bromides and -iodides; dialkylsulfates such asdimethyl-, diethyl-, dibutyl- and diamylsulfates, long chain halidessuch as decyl-, lauryl-, myristyl- and stearylchlorides, -bromides and-iodides, aralkylhalides such as benzyl- and phenethylbromides andothers. Examples of suitable quarternary ammonium ions aretetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, or N-benzyl-N,N,N-trimethylammonium.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

Solvates is the term used for the purposes of the invention for thoseforms of the compounds according to the invention which form a complexwith solvent molecules by coordination in the solid or liquid state.Hydrates are a special form of solvates in which the coordination takesplace with water. Hydrates are preferred as solvates within the scope ofthe present invention.

The invention also includes all suitable isotopic variations of acompound of the invention. An isotopic variation of a compound of theinvention is defined as one in which at least one atom is replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually or predominantly found in nature. Examples ofisotopes that can be incorporated into a compound of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulfur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium),³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S,¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I, respectively. Certainisotopic variations of a compound of the invention, for example, thosein which one or more radioactive isotopes such as ³H or ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionstudies. Tritiated and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. Further,substitution with isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements andhence may be preferred in some circumstances. Isotopic variations of acompound of the invention can generally be prepared by conventionalprocedures known by a person skilled in the art such as by theillustrative methods or by the preparations described in the exampleshereafter using appropriate isotopic variations of suitable reagents.

In addition, the present invention also encompasses prodrugs of thecompounds according to the invention. The term “prodrugs” encompassescompounds which themselves may be biologically active or inactive, butare converted (for example by metabolism or hydrolysis) to compoundsaccording to the invention during their residence time in the body.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorphs, or as a mixture of more than one polymorphs, inany ratio.

Accordingly, the present invention includes all possible salts,polymorphs, metabolites, hydrates, solvates, prodrugs (e.g.: esters)thereof, and diastereoisomeric forms of the compounds of the presentinvention as single salt, polymorph, metabolite, hydrate, solvate,prodrug (e.g.: esters) thereof, or diastereoisomeric form, or as mixtureof more than one salt, polymorph, metabolite, hydrate, solvate, prodrug(e.g.: esters) thereof, or diastereoisomeric form in any ratio.

For the purposes of the present invention, the substituents have thefollowing meaning, unless otherwise specified:

The term “halogen”, “halogen atom” or “halo” represents fluorine,chlorine, bromine and iodine, particularly bromine, chlorine orfluorine, preferably chlorine or fluorine, more preferably fluorine.

The term “alkyl-” represents a linear or branched alkyl- group havingthe number of carbon atoms specifically indicated, e.g. C₁-C₁₀ one, two,three, four, five, six, seven, eight, nine or ten carbon atoms, e.g.methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl-, sec-butyl-,tert-butyl-, pentyl-, isopentyl-, hexyl-, heptyl-, octyl-, nonyl-,decyl-, 2-methylbutyl-, 1-methylbutyl-, 1-ethylpropyl-,1,2-dimethylpropyl-, neo-pentyl-, 1,1-dimethylpropyl-, 4-methylpentyl-,3-methylpentyl-, 2-methylpentyl-, 1-methylpentyl-, 2-ethylbutyl-,1-ethylbutyl-, 3,3-dimethylbutyl-, 2,2-dimethylbutyl-,1,1-dimethylbutyl-, 2,3-dimethylbutyl-, 1,3-dimethylbutyl-, or1,2-dimethylbutyl-. If the number of carbon atoms is not specificallyindicated, the term “alkyl-” represents a linear or branched alkyl-group having, as a rule, 1 to 9, particularly 1 to 6, preferably 1 to 4carbon atoms. Particularly, the alkyl- group has 1, 2, 3, 4, 5 or 6carbon atoms (“C₁-C₆-alkyl-”), e.g. methyl-, ethyl-, n-propyl-,isopropyl-, n-butyl-, tert-butyl-, pentyl-, isopentyl-, hexyl-,2-methylbutyl-, 1-methylbutyl-, 1-ethylpropyl-, 1,2-dimethylpropyl-,neo-pentyl-, 1,1-dimethylpropyl-, 4-methylpentyl-, 3-methylpentyl-,2-methylpentyl-, 1-methylpentyl-, 2-ethylbutyl-, 1-ethylbutyl-,3,3-dimethylbutyl-, 2,2-dimethylbutyl-, 1,1-dimethylbutyl-,2,3-dimethylbutyl-, 1,3-dimethylbutyl-, or 1,2-dimethylbutyl-.Preferably, the alkyl-group has 1, 2 or 3 carbon atoms (“C₁-C₃-alkyl”),methyl-, ethyl-, n-propyl- or isopropyl-.

The term “C₃-C₈-alkylene” is to be understood as preferably meaning alinear, bivalent and saturated hydrocarbon moiety having 3 to 8,particularly 3, 4 or 5 carbon atoms, as in “C₃-C₅-alkylene”, moreparticularly 4 or 5 carbon atoms, as in “C₄-C₅-alkylene” e.g. ethylene,n-propylene, n-butylene, n-pentylene, or n-hexylene, preferablyn-propylene or n-butylene.

The term “C₂-C₆-alkenyl-” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group, which contains onedouble bond, and which has 2, 3, 4, 5 or 6 carbon atoms(“C₂-C₆-alkenyl-”). Particularly, said alkenyl group is aC₂-C₃-alkenyl-, C₃-C₆-alkenyl- or C₃-C₄-alkenyl-group. Said alkenyl-group is, for example, a vinyl-, allyl-, (E)-2-methylvinyl-,(Z)-2-methylvinyl- or isopropenyl- group.

The term “C₂-C₆-alkynyl-” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group which contains onetriple bond, and which contains 2, 3, 4, 5 or 6 carbon atoms.

Particularly, said alkynyl- group is a C₂-C₃-alkynyl-, C₃-C₆-alkynyl- orC₃-C₄-alkynyl- group. Said C₂-C₃-alkynyl- group is, for example, anethynyl-, prop-1-ynyl- or prop-2-ynyl- group.

The term “C₃-C₇-cycloalkyl-” is to be understood as preferably meaning asaturated or partially unsaturated, monovalent, monocyclic hydrocarbonring which contains 3, 4, 5, 6 or 7 carbon atoms. Said C₃-C₇-cycloalkyl-group is for example, a monocyclic hydrocarbon ring, e.g. acyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptyl-group. Said cycloalkyl- ring is non-aromatic but can optionally containone or more double bonds e.g. cycloalkenyl-, such as a cyclopropenyl-,cyclobutenyl-, cyclopentenyl-, cyclohexenyl- or cycloheptenyl- group,wherein the bond between said ring with the rest of the molecule may beto any carbon atom of said ring, be it saturated or unsaturated.Particularly, said cycloalkyl- group is a C₄-C₆-cycloalkyl-, aC₅-C₆-cycloalkyl- or a cyclohexyl- group.

The term “C₃-C₅-cycloalkyl-” is to be understood as preferably meaning asaturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4or 5 carbon atoms. In particular said C₃-C₅-cycloalkyl-group is amonocyclic hydrocarbon ring such as a cyclopropyl-, cyclobutyl- orcyclopentyl- group. Preferably said “C₃-C₅-cycloalkyl-” group is acyclopropyl- group.

The term “C₃-C₄-cycloalkyl-” is to be understood as preferably meaning asaturated, monovalent, monocyclic hydrocarbon ring which contains 3 or 4carbon atoms. In particular, said C₃-C₄-cycloalkyl- group is amonocyclic hydrocarbon ring such as a cyclopropyl- or cyclobutyl- group.

The term “heterocyclyl-” is to be understood as meaning a saturated orpartially unsaturated, monovalent, mono- or bicyclic hydrocarbon ringwhich contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms and further containing1, 2 or 3 heteroatom-containing groups selected from oxygen, sulfur,nitrogen. Particularly, the term “heterocyclyl-” is to be understood asmeaning a “4- to 10-membered heterocyclic ring”.

The term “a 4- to 10-membered heterocyclic ring” is to be understood asmeaning a saturated or partially unsaturated, monovalent, mono- orbicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbonatoms, and further containing 1, 2 or 3 heteroatom-containing groupsselected from oxygen, sulfur, nitrogen.

A C₃-C₉-heterocyclyl- is to be understood as meaning a heterocyclyl-which contains at least 3, 4, 5, 6, 7, 8 or 9 carbon atoms andadditionally at least one heteroatom as ring atoms. Accordingly in caseof one heteroatom the ring is 4- to 10-membered, in case of twoheteroatoms the ring is 5- to 11-membered and in case of threeheteroatoms the ring is 6- to 12-membered.

Said heterocyclic ring is for example, a monocyclic heterocyclic ringsuch as an oxetanyl-, azetidinyl-, tetrahydrofuranyl-, pyrrolidinyl-,1,3-dioxolanyl-, imidazolidinyl-, pyrazolidinyl-, oxazolidinyl-,isoxazolidinyl-, 1,4-dioxanyl-, pyrrolinyl-, tetrahydropyranyl-,piperidinyl-, morpholinyl-, 1,3-dithianyl-, thiomorpholinyl-,piperazinyl-, or chinuclidinyl- group. Optionally, said heterocyclicring can contain one or more double bonds, e.g. 4H-pyranyl-,2H-pyranyl-, 2,5-dihydro-1H-pyrrolyl-, 1,3-dioxolyl-,4H-1,3,4-thiadiazinyl-, 2,5-dihydrofuranyl-, 2,3-dihydrofuranyl-,2,5-dihydrothienyl-, 2,3-dihydrothienyl-, 4,5-dihydrooxazolyl-,4,5-dihydroisoxazolyl-, or 4H-1,4-thiazinyl- group, or, it may be benzofused.

Particularly, a C₃-C₇-heterocyclyl- is to be understood as meaning aheterocyclyl- which contains at least 3, 4, 5, 6, or 7 carbon atoms andadditionally at least one heteroatom as ring atoms. Accordingly in caseof one heteroatom the ring is 4- to 8-membered, in case of twoheteroatoms the ring is 5- to 9-membered and in case of threeheteroatoms the ring is 6- to 10-membered.

Particularly, a C₃-C₆-heterocyclyl- is to be understood as meaning aheterocyclyl- which contains at least 3, 4, 5 or 6 carbon atoms andadditionally at least one heteroatom as ring atoms. Accordingly in caseof one heteroatom the ring is 4- to 7-membered, in case of twoheteroatoms the ring is 5- to 8-membered and in case of threeheteroatoms the ring is 6- to 9-membered.

Particularly, the term “heterocyclyl-” is to be understood as being aheterocyclic ring which contains 3, 4 or 5 carbon atoms, and 1, 2 or 3of the above-mentioned heteroatom-containing groups (a “4- to 8-memberedheterocyclic ring”), more particularly said ring can contain 4 or 5carbon atoms, and 1, 2 or 3 of the above-mentioned heteroatom-containinggroups (a “5- to 8-membered heterocyclic ring”), more particularly saidheterocyclic ring is a “6-membered heterocyclic ring”, which is to beunderstood as containing 4 carbon atoms and 2 of the above-mentionedheteroatom-containing groups or 5 carbon atoms and one of theabove-mentioned heteroatom-containing groups, preferably 4 carbon atomsand 2 of the above-mentioned heteroatom-containing groups.

The term “C₁-C₆-alkoxy-” is to be understood as preferably meaning alinear or branched, saturated, monovalent, hydrocarbon group of formula—O-alkyl-, in which the term “alkyl-” is defined supra, e.g. a methoxy-,ethoxy-, n-propoxy-, iso-propoxy-, n-butoxy-, iso-butoxy-, tert-butoxy-,sec-butoxy-, pentyloxy-, iso-pentyloxy-, n-hexyloxy- group, or an isomerthereof. Particularly, the “C₁-C₆-alkoxy-” group is a “C₁-C₄-alkoxy-”, a“C₁-C₃-alkoxy-”, a methoxy-, ethoxy-, or propoxy- group, preferably amethoxy-, ethoxy- or propoxy- group. Further preferred is a“C₁-C₂-alkoxy-” group, particularly a methoxy- or ethoxy- group.

The term “C₁-C₃-fluoroalkoxy-” is to be understood as preferably meaninga linear or branched, saturated, monovalent, C₁-C₃-alkoxy- group, asdefined supra, in which one or more of the hydrogen atoms is replaced,identically or differently, by one or more fluorine atoms. SaidC₁-C₃-fluoroalkoxy-group is, for example a 1,1-difluoromethoxy-, a1,1,1-trifluoromethoxy-, a 2-fluoroethoxy-, a 3-fluoropropoxy-, a2,2,2-trifluoroethoxy-, a 3,3,3-trifluoropropoxy-, particularly a“C₁-C₂-fluoroalkoxy-” group.

The term “alkylamino-” is to be understood as preferably meaning analkylamino group with one linear or branched alkyl- group as definedsupra. (C₁-C₃)-alkylamino- for example means a monoalkylamino- groupwith 1, 2 oder 3 carbon atoms, (C₁-C₆)-alkylamino- with 1, 2, 3, 4, 5 or6 carbon atoms. The term “alkylamino-” comprises for examplemethylamino-, ethylamino-, n-propylamino-, iso-propylamino-,tert-butylamino-, n-pentylamino- or n-hexylamino-.

The term “,dialkylamino-” is to be understood as preferably meaning analkylamino- group having two linear or branched alkyl- groups as definedsupra, which are independent from each other. (C₁-C₃)-dialkylamino- forexample represents a dialkylamino- group with two alkyl- groups each ofthem having 1 to 3 carbon atoms per alkyl- group. The term“dialkylamino-” comprises for example: N,N-dimethylamino-,N,N-diethylamino-, N-ethyl-N-methylamino-, N-methyl-N-n-propylamino-,N-iso-propyl-N-n-propylamino-, N-tert-butyl-N-methylamino-,N-ethyl-N-n-pentylamino- and N-n-hexyl-N-methylamino-.

The term “cyclic amine” is to be understood as preferably meaning acyclic amine group. Preferably, a cyclic amine means a saturated,monocyclic group with 4 to 10, preferably 4 to 7 ring atoms of which atleast one ring atom is a nitrogen atom. Suitable cyclic amines areespecially azetidine, pyrrolidine, piperidine, piperazine,1-methylpiperazine, morpholine, thiomorpholine, which could beoptionally substituted by one or two methyl groups.

The term “halo-C₁-C₃-alkyl-”, or, used synonymously, “C₁-C₃-haloalkyl-”,is to be understood as preferably meaning a linear or branched,saturated, monovalent hydrocarbon group in which the term “C₁-C₃-alkyl-”is defined supra, and in which one or more hydrogen atoms is replaced bya halogen atom, identically or differently, i.e. one halogen atom beingindependent from another. Preferably, a halo-C₁-C₃-alkyl- group is afluoro-C₁-C₃-alkyl- or a fluoro-C₁-C₂-alkyl- group, such as for example—CF₃, —CHF₂, —CH₂F, —CF₂CF₃, or —CH₂CF₃, more preferably it is —CF₃.

The term “hydroxy-C₁-C₃-alkyl-”, is to be understood as preferablymeaning a linear or branched, saturated, monovalent hydrocarbon group inwhich the term “C₁-C₃-alkyl-” is defined supra, and in which one or morehydrogen atoms is replaced by hydroxy group, preferably not more thanone hydrogen atom per carbon atom being replaced by a hydroxy group.Particularly, a hydroxy-C₁-C₃-alkyl- group is, for example, —CH₂OH,—CH₂—CH₂OH, —C(H)OH—CH₂OH, —CH₂—CH₂—CH₂OH.

The term “phenyl-C₁-C₃-alkyl-” is to be understood as preferably meaninga phenyl group, in which one of the hydrogen atoms is replaced by aC₁-C₃-alkyl group, as defined supra, which links the phenyl-C₁-C₃-alkyl-group to the rest of the molecule. Particularly, the“phenyl-C₁-C₃-alkyl-” is a phenyl-C₁-C₂-alkyl-, preferably it is abenzyl- group.

The term “heteroaryl-” is to be understood as preferably meaning amonovalent, aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or14 ring atoms (a “5- to 14-membered heteroaryl-” group), particularly 5(a “5-membered heteroaryl-”) or 6 (a “6-membered heteroaryl-”) or 9(a“9-membered heteroaryl-”) or 10 ring atoms (a “10-memberedheteroaryl-”), and which contains at least one heteroatom which may beidentical or different, said heteroatom being such as oxygen, nitrogenor sulfur, and can be monocyclic, bicyclic, or tricyclic, and inaddition in each case can be benzo-condensed. Particularly, heteroaryl-is selected from thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-,imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-,triazolyl-, thiadiazolyl-, tetrazolyl- etc., and benzo derivativesthereof, such as, for example, benzofuranyl-, benzothienyl-,benzoxazolyl-, benzisoxazolyl-, benzimidazolyl-, benzotriazolyl-,indazolyl-, indolyl-, isoindolyl-, etc.; or pyridyl-, pyridazinyl-,pyrimidinyl-, pyrazinyl-, triazinyl-, etc., and benzo derivativesthereof, such as, for example, quinolinyl-, quinazolinyl-,isoquinolinyl-, etc.; or azocinyl-, indolizinyl-, purinyl-, etc., andbenzo derivatives thereof; or cinnolinyl-, phthalazinyl-, quinazolinyl-,quinoxalinyl-, naphthyridinyl-, pteridinyl-, carbazolyl-, acridinyl-,phenazinyl-, phenothiazinyl-, phenoxazinyl-, xanthenyl-, or oxepinyl-,etc. Preferably, heteroaryl- is selected from monocyclic heteroaryl-,5-membered heteroaryl- or 6-membered heteroaryl-.

The term “5-membered heteroaryl-” is understood as preferably meaning amonovalent, aromatic ring system having 5 ring atoms and which containsat least one heteroatom which may be identical or different, saidheteroatom being such as oxygen, nitrogen or sulfur. Particularly,“5-membered heteroaryl-” is selected from thienyl-, furanyl-, pyrrolyl-,oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-,isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, tetrazolyl-.

The term “6-membered heteroaryl-” is understood as preferably meaning amonovalent, aromatic ring system having 6 ring atoms and which containsat least one heteroatom which may be identical or different, saidheteroatom being such as oxygen, nitrogen or sulfur. Particularly,“6-membered heteroaryl-” is selected from pyridyl-, pyridazinyl-,pyrimidinyl-, pyrazinyl-, triazinyl-.

The term “heteroaryl-C₁-C₃-alkyl-” is to be understood as preferablymeaning a heteroaryl-, a 5-membered heteroaryl- or a 6-memberedheteroaryl- group, each as defined supra, in which one of the hydrogenatoms is replaced by a C₁-C₃-alkyl- group, as defined supra, which linksthe heteroaryl-C₁-C₃-alkyl- group to the rest of the molecule.Particularly, the “heteroaryl-C₁-C₃-alkyl-” is aheteroaryl-C₁-C_(r)-alkyl-, a pyridinyl-C₁-C₃-alkyl-, apyridinylmethyl-, a pyridinylethyl-, a pyridinylpropyl-, apyrimidinyl-C₁-C₃-alkyl-, a pyrimidinylmethyl-, a pyrimidinylethyl-, apyrimidinylpropyl-, preferably a pyridinylmethyl- or a pyridinylethyl-or a pyrimidinylethyl- or a pyrimidinylpropyl- group.

As used herein, the term “leaving group” refers to an atom or a group ofatoms that is displaced in a chemical reaction as stable species takingwith it the bonding electrons. Preferably, a leaving group is selectedfrom the group comprising: halo, in particular a chlorine atom, abromine atom or an iodine atom, methanesulfonyloxy-,p-toluenesulfonyloxy-, trifluoromethanesulfonyloxy-,nonafluorobutanesulfonyloxy-, (4-bromo-benzene)sulfonyloxy-,(4-nitro-benzene)sulfonyloxy-, (2-nitro-benzene)-sulfonyloxy-,(4-isopropyl-benzene)sulfonyloxy-,(2,4,6-tri-isopropyl-benzene)-sulfonyloxy-,(2,4,6-trimethyl-benzene)sulfonyloxy-,(4-tert-butyl-benzene)sulfonyloxy-, benzenesulfonyloxy-, and(4-methoxy-benzene)sulfonyloxy-.

As used herein, the term “C₁-C₃-alkylbenzene” refers to a partiallyaromatic hydrocarbon consisting of a benzene ring which is substitutedby one or two C₁-C₃-alkyl- groups, as defined supra. Particularly,“C₁-C₃-alkylbenzene” is toluene, ethylbenzene, cumene, n-propylbenzene,ortho-xylene, meta-xylene or para-xylene. Preferably,“C₁-C₃-alkylbenzene” is toluene.

As used herein, the term “carboxamide based solvent” refers to loweraliphatic carboxamides of the formula C₁-C₂-alkyl-C(═O)—N(C₁-C₂-alkyl)₂,or lower cyclic aliphatic carboxamides of the formula

in which G represents —CH₂—, —CH₂—CH₂— or —CH₂—CH₂—CH₂—. Particularly,“carboxamide based solvent” is N,N-dimethylformamide,N,N-dimethylacetamide or N-methylpyrrolidin-2-one. Preferably,“carboxamide based solvent” is N,N-dimethylformamide orN-methyl-pyrrolidin-2-one.

The term “C₁-C₁₀”, as used throughout this text, e.g. in the context ofthe definition of “C₁-C₁₀-alkyl” is to be understood as meaning an alkylgroup having a finite number of carbon atoms of 1 to 10, i.e. 1, 2, 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms. It is to be understood further thatsaid term “C₁-C₁₀” is to be interpreted as any sub-range comprisedtherein, e.g. C₁-C₁₀, C₁-C₉, C₁-C₈, C₁-C₇, C₁-C₆ C₁-C₅, C₁-C₄, C₁-C₃,C₁-C₂, C₂-C₁₀, C₂-C₉, C₂-C₈, C₂-C₇, C₂-C₆, C₂-C₅, C₂-C₄, C₂-C₃, C₃-C₁₀,C₃-C₉, C₃-C₈, C₃-C₇, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₁₀, C₄-C₉, C₄-C₈, C₄-C₇,C₄-C₆, C₄-C₅, C₅-C₁₀, C₅-C₉, C₅-C₈, C₅-C₇, C₅-C₆, C₆-C₁₀, C₆-C₉, C₆-C₈,C₆-C₇, C₇-C₁₀, C₇-C₉, C₇-C₈, C₈-C₁₀, C₈-C₉, C₉-C₁₀.

Similarly, as used herein, the term “C₁-C₆”, as used throughout thistext, e.g. in the context of the definition of “C₁-C₆-alkyl”,“C₁-C₆-alkoxy” is to be understood as meaning an alkyl group having afinite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbonatoms. It is to be understood further that said term “C₁-C₆” is to beinterpreted as any sub-range comprised therein, e.g. C₁-C₆ C₁-C₅, C₁-C₄,C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅, C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆,C₄-C₅, C₅-C₆.

Similarly, as used herein, the term “C₁-C₄”, as used throughout thistext, e.g. in the context of the definition of “C₁-C₄-alkyl”,“C₁-C₄-alkoxy” is to be understood as meaning an alkyl group having afinite number of carbon atoms of 1 to 4, i.e. 1, 2, 3 or 4 carbon atoms.It is to be understood further that said term “C₁-C₄” is to beinterpreted as any sub-range comprised therein, e.g. C₁-C₄, C₁-C₃,C₁-C₂, C₂-C₄, C₂-C₃, C₃-C₄.

Similarly, as used herein, the term “C₁-C₃”, as used throughout thistext, e.g. in the context of the definition of “C₁-C₃-alkyl”,“C₁-C₃-alkoxy” or “C₁-C₃-fluoroalkoxy” is to be understood as meaning analkyl group having a finite number of carbon atoms of 1 to 3, i.e. 1, 2or 3 carbon atoms. It is to be understood further that said term “C₁-C₃”is to be interpreted as any sub-range comprised therein, e.g. C₁-C₃,C₁-C₂, C₂-C₃.

Further, as used herein, the term “C₃-C₆”, as used throughout this text,e.g. in the context of the definition of “C₃-C₆-cycloalkyl”, is to beunderstood as meaning a cycloalkyl group having a finite number ofcarbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to beunderstood further that said term “C₃-C₆” is to be interpreted as anysub-range comprised therein, e.g. C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅,C₅-C₆. Further, as used herein, the term “C₃-C₇”, as used throughoutthis text, e.g. in the context of the definition of “C₃-C₇-cycloalkyl”,is to be understood as meaning a cycloalkyl group having a finite numberof carbon atoms of 3 to 7, i.e. 3, 4, 5, 6 or 7 carbon atoms,particularly 3, 4, 5 or 6 carbon atoms. It is to be understood furtherthat said term “C₃-C₇” is to be interpreted as any sub-range comprisedtherein, e.g. C₃-C₇, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₇, C₄-C₆, C₄-C₅, C₅-C₇,C₅-C₆, C₆-C₇.

A symbol

at a bond denotes the linkage site in the molecule.

As used herein, the term “one or more times”, e.g. in the definition ofthe substituents of the compounds of the general formulae of the presentinvention, is understood as meaning one, two, three, four or five times,particularly one, two, three or four times, more particularly one, twoor three times, even more particularly one or two times.

Where the plural form of the word compounds, salts, hydrates, solvatesand the like, is used herein, this is taken to mean also a singlecompound, salt, isomer, hydrate, solvate or the like.

In another embodiment, the present invention concerns compounds ofgeneral formula (I), wherein

-   A represents a bivalent moiety selected from the group consisting of    —S—, —S(═O)—, —S(═O)₂—, —S(═O)(═NR⁵)—; —S(═NR⁶)(═NR⁷)—;-   Z represents a hydrogen atom or a fluorine atom;-   L represents a C₃-C₅-alkylene moiety,    -   wherein said moiety is optionally substituted with    -   i) one substituent selected from hydroxy, C₃-C₄-cycloalkyl-,        hydroxy-C₁-C₃-alkyl-, —(CH₂)NR⁸R⁹, and/or    -   ii) one or two or three substituents, identically or        differently, selected from halogen and C₁-C₃-alkyl-;-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a group selected from C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-,    wherein said group is optionally substituted with one or two or    three substituents, identically or differently, selected from the    group consisting of hydroxy, cyano, halogen, C₁-C₃-alkyl-,    fluoro-C₁-C₂-alkyl-, C₁-C₃-alkoxy-, C₁-C₂-fluoroalkoxy-, —NH₂,    alkylamino-, dialkylamino-, cyclic amines, —OP(═O)(OH)₂, —C(═O)OH,    —C(═O)NH₂;-   R² represents a group selected from a hydrogen atom, a fluorine    atom, a chlorine atom, cyano, C₁-C₂-alkyl-, C₁-C₂-alkoxy-,    fluoro-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-;-   R³, R⁴ represent, independently from each other, a group selected    from a hydrogen atom, a fluorine atom, a chlorine atom, cyano,    C₁-C₂-alkyl-, C₁-C₂-alkoxy-, fluoro-C₁-C₂-alkyl-,    C₁-C₂-fluoroalkoxy-;-   R⁵ represents a group selected from a hydrogen atom, cyano,    —C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O)₂R¹⁰, —C(═O)NR⁸R⁹, C₁-C₆-alkyl-,    C₃-C₅-cycloalkyl-,    -   wherein said C₁-C₆-alkyl- or C₃-C₅-cycloalkyl- group is        optionally substituted with one, two or three substituents,        identically or differently, selected from the group consisting        of halogen, hydroxy, cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂,        alkylamino-, dialkylamino-, cyclic amines, fluoro-C₁-C₂-alkyl-,        C₁-C₂-fluoroalkoxy-;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, cyano, —C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O)₂R¹⁰,    —C(═O)NR⁸R⁹, C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-,    -   wherein said C₁-C₆-alkyl- or C₃-C₅-cycloalkyl- group is        optionally substituted with one, two or three substituents,        identically or differently, selected from the group consisting        of halogen, hydroxy, cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂,        alkylamino-, dialkylamino-, cyclic amines, fluoro-C₁-C₂-alkyl-,        C₁-C₂-fluoroalkoxy-;-   R⁸, R⁹ represent, independently from each other, a group selected    from a hydrogen atom, C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-, phenyl- and    benzyl-,    -   wherein said C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-, phenyl- or benzyl-        group is optionally substituted with one, two or three        substituents, identically or differently, selected from the        group consisting of halogen, hydroxy, C₁-C₃-alkyl-,        C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, cyclic amines,        fluoro-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-, or-   R⁸ and R⁹, together with the nitrogen atom they are attached to,    form a cyclic amine;-   R¹⁰ represents a group selected from C₁-C₆-alkyl-,    fluoro-C₁-C₃-alkyl-, C₃-C₅-cycloalkyl-, phenyl-, and benzyl-,    -   wherein said group is optionally substituted with one, two or        three substituents, identically or differently, selected from        the group consisting of halogen, hydroxy, C₁-C₃-alkyl-,        C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, cyclic amines,        fluoro-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-        or the enantiomers, diastereomers, salts, solvates or salts of        solvates thereof.

In another embodiment, the present invention concerns compounds ofgeneral formula (I), wherein

-   A represents a bivalent moiety selected from the group consisting of    —S—, —S(═O)—, —S(═O)₂—, —S(═O)(═NR⁵)—; —S(═NR⁶)(═NR⁷)—;-   Z represents a hydrogen atom or a fluorine atom;-   L represents a C₃-C₅-alkylene moiety,    -   wherein said moiety is optionally substituted with    -   (i) one substituent selected from C₃-C₄-cycloalkyl-,        hydroxymethyl, and/or    -   (ii) one or two or three C₁-C₂-alkyl- group substituents,        identically or differently;-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a group selected from C₁-C₄-alkyl-, C₃-C₅-cycloalkyl-,    wherein said group is optionally substituted with one or two or    three substituents, identically or differently, selected from the    group consisting of hydroxy, cyano, halogen, C₁-C₂-alkyl-,    C₁-C₂-alkoxy-, —NH₂, —C(═O)OH;-   R² represents a group selected from a hydrogen atom, a fluorine    atom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-,    trifluoromethoxy-;-   R³ represents a group selected from a hydrogen atom, a fluorine    atom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-,    trifluoromethoxy-;-   R⁴ represents a hydrogen atom or a fluorine atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    —C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O)₂R¹⁰, —C(═O)NR⁸R⁹, C₁-C₄-alkyl-,    -   wherein said C₁-C₄-alkyl- group is optionally substituted with        one substituent selected from the group consisting of a fluorine        atom, hydroxy, cyano, C₁-C₃-alkoxy-, —NH₂, alkylamino-,        dialkylamino-, cyclic amines;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, cyano, —C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O)₂R¹⁰,    —C(═O)NR⁸R⁹, C₁-C₄-alkyl-,    -   wherein said C₁-C₄-alkyl- group is optionally substituted with        one substituent selected from the group consisting of a fluorine        atom, hydroxy, cyano, C₁-C₃-alkoxy-, —NH₂, alkylamino-,        dialkylamino-, cyclic amines;-   R⁸, R⁹ represent, independently from each other, a group selected    from a hydrogen atom, C₁-C₄-alkyl- and C₃-C₅-cycloalkyl-;    -   wherein said C₁-C₄-alkyl- or C₃-C₅-cycloalkyl- group is        optionally substituted with one or two substituents, identically        or differently, selected from the group consisting of hydroxy,        C₁-C₂-alkyl-, C₁-C₂-alkoxy-, —NH₂, alkylamino-, dialkylamino-,        cyclic amines, or-   R⁸ and R⁹, together with the nitrogen atom they are attached to,    form a cyclic amine;-   R¹⁰ represents a group selected from C₁-C₆-alkyl-,    fluoro-C₁-C₃-alkyl-, C₃-C₅-cycloalkyl- and benzyl-,    -   wherein said group is optionally substituted with one        substituent selected from the group consisting of halogen,        hydroxy, C₁-C₂-alkyl-, C₁-C₂-alkoxy-, —NH₂,        or the enantiomers, diastereomers, salts, solvates or salts of        solvates thereof.

In a preferred embodiment, the present invention concerns compounds ofgeneral formula (I), wherein

-   A represents a bivalent moiety selected from the group consisting of    —S—, —S(═O)—, —S(═O)₂—, —S(═O)(═NR⁵)—, —S(═NR⁶)(═NR⁷)—;-   Z represents a hydrogen atom or a fluorine atom;-   L represents a C₃-C₅-alkylene moiety;-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a C₁-C₄-alkyl-group,    -   wherein said group is optionally substituted with one or two        substituents, identically or differently, selected from the        group consisting of hydroxy, C₁-C₂-alkoxy-, —NH₂, —C(═O)OH;-   R² represents a hydrogen atom or a fluorine atom;-   R³ represents a group selected from a hydrogen atom, a fluorine atom    and a methoxy- group;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    —C(═O)R¹⁰, —C(═O)OR¹⁰, —C(═O)NR⁸R⁹, C₁-C₄-alkyl-,    -   wherein said C₁-C₄-alkyl- group is optionally substituted with        one substituent selected from the group consisting of hydroxy,        cyano, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, cyano, C₁-C₄-alkyl-,    -   wherein said C₁-C₄-alkyl- group is optionally substituted with        one hydroxy group;-   R⁸, R⁹ represent, independently from each other, a group selected    from a hydrogen atom, C₁-C₄-alkyl- and C₃-C₅-cycloalkyl-, or-   R⁸ and R⁹, together with the nitrogen atom they are attached to,    form a cyclic amine;-   R¹⁰ represents a group selected from C₁-C₆-alkyl-,    fluoro-C₁-C₃-alkyl-, C₃-C₅-cycloalkyl- and benzyl-,    -   wherein said group is optionally substituted with one        substituent selected from the group consisting of halogen,        hydroxy, C₁-C₂-alkyl-, C₁-C₂-alkoxy-, —NH₂,        or the enantiomers, diastereomers, salts, solvates or salts of        solvates thereof.

In another preferred embodiment, the present invention concernscompounds of general formula (I), wherein

-   A represents a bivalent moiety selected from the group consisting of    —S(═O)₂—, —S(═O)(═NR⁵)—, —S(═NR⁶)(═NR⁷)—;-   Z represents a hydrogen atom or a fluorine atom;-   L represents a C₃-C₅-alkylene moiety,-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a methyl- group;-   R² represents a hydrogen atom;-   R³ represents a group selected from a hydrogen atom or a fluorine    atom;-   R⁴ represents a hydrogen atom;-   R⁵ represent a group selected from a hydrogen atom, cyano,    —C(═O)R¹⁰, —C(═O)OR¹⁰, C₁-C₄-alkyl-,    -   wherein said C₁-C₄-alkyl- group is optionally substituted with        one substituent selected from the group consisting of hydroxy,        cyano, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-;-   R⁶, R⁷ represents, independently from each other, a group selected    from a hydrogen atom, cyano, C₁-C₄-alkyl-,    -   wherein said C₁-C₄-alkyl- group is optionally substituted with        one hydroxy group;-   R⁸, R⁹ represent, independently from each other, a group selected    from a hydrogen atom, C₁-C₂-alkyl;-   R¹⁰ represents a C₁-C₄-alkyl group,    or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another preferred embodiment, the present invention concernscompounds of general formula (I), wherein

-   A represents a bivalent moiety selected from the group consisting of    —S—, —S(═O)—, —S(═O)₂—, —S(═O)(═NR⁵)—;-   Z represents a hydrogen atom or a fluorine atom;-   L represents a C₃-C₅-alkylene moiety;-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a C₁-C₃-alkyl- group;-   R² represents a hydrogen atom or a fluorine atom;-   R³ represents a group selected from a hydrogen atom, a fluorine atom    and a methoxy- group;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    —C(═O)R¹⁰, —C(═O)OR¹⁰, C₁-C₃-alkyl-;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, cyano, —C(═O)R¹⁰, —C(═O)OR¹⁰, C₁-C₃-alkyl-;-   R¹⁰ represents a group selected from C₁-C₄-alkyl-, trifluoromethyl-    and benzyl-,    or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another preferred embodiment, the present invention concernscompounds of general formula (I), wherein

-   A represents a bivalent moiety selected from the group consisting of    —S—, —S(═O)—, —S(═O)₂—, —S(═O)(═NR⁵)—, —S(═NR⁶)(═NR⁷)—;-   Z represents a group selected from a hydrogen atom and a fluorine    atom;-   L represents a C₄-C₅-alkylene moiety;-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a methyl- group;-   R² represents a hydrogen atom;-   R³ represents a hydrogen atom or a fluorine atom;-   R⁴ represents a hydrogen atom;-   R⁸ represents a group selected from a hydrogen atom, —C(═O)OR¹⁰;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, —C(═O)OR¹⁰;-   R¹⁰ represents a group selected from tert-butyl- and benzyl-,    the enantiomers, diastereomers, salts, solvates or salts of solvates    thereof.

In another preferred embodiment, the present invention concernscompounds of general formula (I), wherein

-   Z represents a group selected from a hydrogen atom and a fluorine    atom,-   R³ represents a fluorine atom, and-   R⁴ represents a hydrogen atom,    or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another preferred embodiment, the present invention concernscompounds of general formula (I), wherein

-   A represents a bivalent moiety —S(═O)(═NR⁵)—;-   Z represents a group selected from a hydrogen atom and a fluorine    atom,-   L represents a C₃-C₅-alkylene moiety;-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a methyl- group;-   R² represents a hydrogen atom;-   R³ represents a fluorine atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a hydrogen atom or a —C(═O)OR¹⁰— group;-   R¹⁰ represents a tertbutyl- group;    or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In particular, a preferred subject of the present invention is acompound selected from:

-   (rac)-tert-butyl    [{[3,20-difluoro-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate-   (rac)-3,20-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene-   (rac)-tert-butyl    [{[3,20-difluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate-   (rac)-3,20-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene-   (rac)-tert-butyl    [{[3,21-difluoro-13,19-dioxa-5,7,26-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaen-10-yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate-   (rac)-3,21-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,7,26-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene-   (rac)-tert-butyl    [methyl(oxido){[3,20,23-trifluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}-1λ⁶-sulfanylidene]carbamate-   (rac)-3,20,23-trifluoro-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene-   (rac)-tert-butyl    [{[3,19-difluoro-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1^(2,6).1^(8,12)]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaen-10-yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate-   (rac)-3,19-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1^(2,6).1^(8,12)]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaene-   (rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene-   Enantiomer 1 of    (rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene-   Enantiomer 2 of    (rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene-   Diastereoisomer 1 of    3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene-   Diastereoisomer 2 of    3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene-   Diastereoisomer 3 of    3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene-   Diastereoisomer 4 of    3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene-   (rac)-3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene-   Enantiomer 1 of    3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene-   Enantiomer 2 of    3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene-   Mixture of diastereoisomers 1 and 2 of    3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene-   Mixture of diastereoisomers 3 and 4 of    3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene-   (rac)-3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene-   Enantiomer 1 of    3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene-   Enantiomer 2 of    3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene-   Mixture of diastereoisomers 1 and 2 of    3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene-   Mixture of diastereoisomers 3 and 4 of    3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene-   Mixture of enantiomers of    3,20-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene-   Enantiomer 1 of    3,21-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene-   Enantiomer 2 of    3,21-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene-   Enantiomer 1 of    3,22-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]hexacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene-   Enantiomer 2 of    3,22-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]hexacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene    and the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

The invention relates to compounds of formula (I), in which A representsa bivalent moiety selected from the group consisting of —S—, —S(═O)—,—S(═O)₂—, —S(═O)(═NR⁵)—; —S(═NR⁶)(═NR⁷)—.

In another embodiment the invention relates to compounds of formula (I),in which A represents a bivalent moiety —S(═O)₂—, —S(═O)(═NR⁵)—,—S(═NR⁶)(═NR⁷)—.

In another embodiment the invention relates to compounds of formula (I),in which A represents a bivalent moiety selected from the groupconsisting of —S—, —S(═O)—, —S(═O)₂—, —S(═O)(═NR)—.

In a preferred embodiment the invention relates to compounds of formula(I), in which A represents a bivalent moiety selected from the groupconsisting of —S—, —S(═O)—, —S(═O)(═NR⁵)—, —S(═NR⁶)(═NR⁷)—.

In another preferred embodiment the invention relates to compounds offormula (I), in which A represents a bivalent moiety —S(═O)(═NR⁵)—,—S(═NR⁶)(═NR⁷)—.

In another preferred embodiment the invention relates to compounds offormula (I), in which A represents a bivalent moiety —S(═NR⁶)(═NR⁷)—.

In another preferred embodiment the invention relates to compounds offormula (I), in which A represents a bivalent moiety —S(═NH)(═NH)—.

In another preferred embodiment the invention relates to compounds offormula (I), in which A represents a bivalent moiety —S(═O)₂—.

In another preferred embodiment the invention relates to compounds offormula (I), in which A represents a bivalent moiety —S(═O)(═NR⁵)—.

In another preferred embodiment the invention relates to compounds offormula (I), in which A represents a bivalent moiety—S(═O)(═N—C(═O)O—C(CH₃)₃)—.

In another preferred embodiment the invention relates to compounds offormula (I), in which A represents a bivalent moiety —S(═O)(═NCH₃)—.

In another preferred embodiment the invention relates to compounds offormula (I), in which A represents a bivalent moiety —S(═O)(═NH)—.

In another embodiment the invention relates to compounds of formula (I),in which Z represents a hydrogen atom or a fluorine atom.

In a preferred embodiment the invention relates to compounds of formula(I), in which Z represents a fluorine atom.

In another preferred embodiment the invention relates to compounds offormula (I), in which Z represents a hydrogen atom.

The invention relates to compounds of formula (I), in which L representsa C₃-C₅ alkylene moiety,

wherein said moiety is optionally substituted with

-   i) one substituent selected from hydroxy, —NR⁸R⁹, C₂-C₃-alkenyl-,    C₂-C₃-alkynyl-, C₃-C₄ cycloalkyl-, hydroxy-C₁-C₃-alkyl, —(CH₂)NR⁸R⁹,    and/or-   ii) one or two or three or four substituents, identically or    differently, selected from halogen and C₁-C₃-alkyl-,    or wherein    one carbon atom of said C₃-C₅-alkylene moiety forms a three- or    four-membered ring together with a bivalent moiety to which it is    attached, wherein said bivalent moiety is selected from —CH₂CH₂—,    —CH₂CH₂CH₂—, —CH₂OCH₂—.

In a another embodiment the invention relates to compounds of formula(I), in which L represents a C₃-C₅-alkylene moiety,

wherein said moiety is optionally substituted with

-   i) one substituent selected from hydroxy, C₃-C₄-cycloalkyl-,    hydroxy-C₁-C₃-alkyl-, —(CH₂)NR⁸R⁹, and/or-   ii) one or two or three substituents, identically or differently,    selected from halogen and C₁-C₃-alkyl-.

In a another embodiment the invention relates to compounds of formula(I), in which L represents a C₃-C₅-alkylene moiety,

wherein said moiety is optionally substituted with

-   (i) one substituent selected from C₃-C₄-cycloalkyl-, hydroxymethyl,    and/or-   (ii) one or two or three substituents, identically or differently,    selected from C₁-C₂-alkyl-.

In a preferred embodiment the invention relates to compounds of formula(I), in which L represents a C₃-C₅-alkylene moiety.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which L represents a C₄-C₅-alkylene moiety.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which L represents a moiety —CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂CH₂—.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which L represents a moiety —CH₂CH₂CH₂—.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which L represents a moiety —CH₂CH₂CH₂CH₂—.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which L represents a moiety—CH₂CH₂CH₂CH₂CH₂—.

The invention relates to compounds of formula (I, in which X, Yrepresent CH or N with the proviso that one of X and Y represents CH andone of X and Y represents N.

In another embodiment the invention relates to compounds of formula (I),in which X represents N, and in which Y represents CH.

In another embodiment the invention relates to compounds of formula (I),in which X represents CH, and in which Y represents N.

The invention relates to compounds of formula (I), in which R¹represents a group selected from C₁-C₆-alkyl-, C₃-C₆-alkenyl-,C₃-C₇-cycloalkyl-, heterocyclyl-,

wherein said group is optionally substituted with one or two or threesubstituents, identically or differently, selected from the groupconsisting of hydroxy, cyano, halogen, C₁-C₆-alkyl-, halo-C₁-C₃-alkyl-,C₁-C₆-alkoxy-, C₁-C₃-fluoroalkoxy-, —NH₂, alkylamino-, dialkylamino-,acetylamino-, N-methyl-N-acetylamino-, cyclic amines, —OP(═O)(OH)₂,—C(═O)OH, —C(═O)NH₂.

In another embodiment the invention relates to compounds of formula (I),in which R¹ represents a group selected from C₁-C₆-alkyl-,C₃-C₅-cycloalkyl-,

wherein said group is optionally substituted with one or two or threesubstituents, identically or differently, selected from the groupconsisting of hydroxy, cyano, halogen, C₁-C₃-alkyl-,fluoro-C₁-C₂-alkyl-, C₁-C₃-alkoxy-, C₁-C₂-fluoroalkoxy-, —NH₂,alkylamino-, dialkylamino-, cyclic amines, —OP(═O)(OH)₂, —C(═O)OH,—C(═O)NH₂.

In a preferred embodiment the invention relates to compounds of formula(I), in which R¹ represents a group selected from C₁-C₄-alkyl-,C₃-C₅-cycloalkyl-,

wherein said group is optionally substituted with one or two or threesubstituents, identically or differently, selected from the groupconsisting of hydroxy, cyano, halogen, C₁-C₂-alkyl-, C₁-C₂-alkoxy-,—NH₂, —C(═O)OH.

In a preferred embodiment the invention relates to compounds of formula(I), in which R¹ represents a C₁-C₄-alkyl-group,

wherein said group is optionally substituted with one or twosubstituents, identically or differently, selected from the groupconsisting of hydroxy, C₁-C₂-alkoxy-, —NH₂, —C(═O)OH.

In a preferred embodiment the invention relates to compounds of formula(I), in which R¹ represents a C₁-C₄-alkyl- group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R¹ represents a C₁-C₃-alkyl- group.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R¹ represents a C₁-C₂-alkyl- group.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R¹ represents a methyl- group.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R¹ represents a C₁-C₄-alkyl- group,and R² represents a hydrogen atom or a fluoro atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R¹ represents a C₁-C₄-alkyl- group,and R² represents a hydrogen atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R¹ represents a methyl group, and R²represents a hydrogen atom.

R¹ is bound in all compounds according to the present invention to thesulfur atom of the group A.

The invention relates to compounds of formula (I), in which R²represents a group selected from a hydrogen atom, a fluorine atom, achlorine atom, a bromine atom, cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-,halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R² represents a group selected from a hydrogen atom, a fluorineatom, a chlorine atom, cyano, C₁-C₂-alkyl-, C₁-C₂-alkoxy-,fluoro-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-.

In a preferred embodiment the invention relates to compounds of formula(I), in which R² represents a group selected from a hydrogen atom, afluorine atom, a chlorine atom, cyano, methyl-, methoxy-,trifluoromethyl-, trifluoromethoxy-.

In another preferred embodiment the invention relates to compounds offormula (I), in which R² represents a hydrogen atom or a fluorine atom.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R² represents a fluorine atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R² represents a hydrogen atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R² represents a hydrogen atom, R³represents a fluorine atom, R⁴ represents a hydrogen atom and Zrepresents a hydrogen atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R¹ represents a methyl- group, R²represents a hydrogen atom, R³ represents a fluorine atom, R⁴ representsa hydrogen atom and Z represents a hydrogen atom.

The invention relates to compounds of formula (I), in which R³, R⁴represent, independently from each other, a group selected from ahydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, cyano,C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R³, R⁴ represent, independently from each other, a groupselected from a hydrogen atom, a fluorine atom, a chlorine atom, cyano,C₁-C₂-alkyl-, C₁-C₂-alkoxy-, fluoro-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R³, R⁴ represent, independently from each other, a groupselected from a hydrogen atom, a fluorine atom, a chlorine atom, cyano,methyl-, methoxy-, trifluoromethyl-, trifluoromethoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R³, R⁴ represent, independently from each other, a groupselected from a hydrogen atom or a fluorine atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, cyano, C₁-C₃-alkyl-,C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy and in which R⁴represents a hydrogen atom or a fluorine atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, cyano, C₁-C₂-alkyl-,C₁-C₂-alkoxy-, halo-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy and in which R⁴represents a hydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom, a fluorineatom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-,trifluoromethoxy- and in which R⁴ represents a hydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom, a fluorineatom and a methoxy- group an in which R⁴ represents a hydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom or afluorine atom and in which R⁴ represents a hydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a fluorine atom and in which R⁴ represents ahydrogen atom.

In a preferred embodiment the invention relates to compounds of formula(I), in which R³ represents a group selected from a hydrogen atom, afluorine atom, a chlorine atom, cyano, methyl-, methoxy-,trifluoromethyl-, trifluoromethoxy-.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R³ represents a hydrogen atom or afluorine atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R³ represents a fluorine atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R³ represents a hydrogen atom.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁴ represents a group selected from a hydrogen atom, afluorine atom, a chlorine atom, cyano, methyl-, methoxy-,trifluoromethyl-, trifluoromethoxy-.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁴ represents a hydrogen atom or afluorine atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁴ represents a fluorine atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁴ represents a hydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom, a fluorineatom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-,trifluoromethoxy-, in which R⁴ represents a hydrogen atom, and in whichZ represents a hydrogen atom or a fluorine atom,

wherein R³ is attached in para-position to the ring directly bonded tothe phenyl-ring to which R³ is attached, which is a pyridine ring if Yrepresents CH and a pyrimidine ring if Y represents N.

In a preferred embodiment the invention relates to compounds of formula(I), in which R³ represents a hydrogen atom or a fluorine atom, in whichR⁴ represents a hydrogen atom, and in which Z represents a hydrogen atomor a fluorine atom,

wherein R³ is attached in para-position to the ring directly bonded tothe phenyl-ring to which R³ is attached, which is a pyridine ring if Yrepresents CH and a pyrimidine ring if Y represents N.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R³ represents a fluorine atom, inwhich R⁴ represents a hydrogen atom, and in which Z represents ahydrogen atom,

wherein R³ is attached in para-position to the ring directly bonded tothe phenyl-ring to which R³ is attached, which is a pyridine ring if Yrepresents CH and a pyrimidine ring if Y represents N.

In a preferred embodiment the invention relates to compounds of formula(I), in which R³ represents a fluorine atom, in which R⁴ represents ahydrogen atom, and in which Z represents a hydrogen atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R³ represents a fluorine atom,

wherein R³ is attached in para-position to the ring directly bonded tothe phenyl-ring to which R³ is attached, which is a pyridine ring if Yrepresents CH and a pyrimidine ring if Y represents N.

The invention relates to compounds of formula (I), in which R⁵represents a group selected from a hydrogen atom, cyano, —C(═O)R¹⁰,—C(═O)OR¹⁰, —S(═O₂)R¹⁰, —C(═O)NR⁸R⁹, C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-,heterocyclyl-,

wherein said C₁-C₆-alkyl-, C₃-C₇-cycloalkyl- and heterocyclyl- group isoptionally substituted with one, two or three substituents, identicallyor differently, selected from the group consisting of halogen, hydroxy,cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-,acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a group selected from a hydrogen atom, cyano,—C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O)₂R¹⁰, —C(═O)NR⁸R⁹, C₁-C₆-alkyl-,C₃-C₅-cycloalkyl-,

wherein said C₁-C₆-alkyl- and C₃-C₅-cycloalkyl- group is optionallysubstituted with one, two or three substituents, identically ordifferently, selected from the group consisting of halogen, hydroxy,cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-,cyclic amines, fluoro-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁵ represents a group selected from a hydrogen atom,cyano, —C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O)₂R¹⁰, —C(═O)NR⁸R⁹, C₁-C₄-alkyl-,

wherein said C₁-C₄-alkyl- group is optionally substituted with onesubstituent selected from the group consisting of a fluorine atom,hydroxy, cyano, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, cyclicamines.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁵ represents a group selected from a hydrogenatom, cyano, —C(═O)R¹⁰, —C(═O)OR¹⁰, —C(═O)NR⁸R⁹, C₁-C₄-alkyl-, whereinsaid C₁-C₄-alkyl- group is optionally substituted with one substituentselected from the group consisting of hydroxy, cyano, C₁-C₃-alkoxy-,—NH₂, alkylamino-, dialkylamino-.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁵ represents a group selected from a hydrogenatom, cyano, —C(═O)R¹⁰, —C(═O)OR¹⁰, C₁-C₄-alkyl-,

wherein said C₁-C₄-alkyl- group is optionally substituted with onesubstituent selected from the group consisting of hydroxy, cyano,C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁵ represents a group selected from a hydrogen atom,cyano, —C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O)₂R¹⁰, —C(═O)NR⁸R⁹, C₁-C₄-alkyl-.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁵ represents a group selected from a hydrogen atom,—C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O)₂R¹⁰, —C(═O)NR⁸R⁹, C₁-C₄-alkyl-.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁵ represents a group selected from ahydrogen atom, —C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O)₂R¹⁰, —C(═O)NR⁸R⁹, methyl-.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁵ represents a —C(═O)OR¹⁰ group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁵ represents a —C(═O)R¹⁰ group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁵ represents a —S(═O)₂R¹⁰ group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁵ represents C₁-C₄-alkyl- group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁵ represents methyl- group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁵ represents a cyano group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁵ represents a —C(═O)NR⁸R⁹ group.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R represents a —C(═O)O—C(CH₃)₃)group.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁵ represents a hydrogen atom.

The invention relates to compounds of formula (I), in which R⁶ and R⁷,independently from each other represent a group selected from a hydrogenatom, cyano, —C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O)₂R¹⁰, —C(═O)NR⁸R⁹,C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-,

wherein said C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl- group isoptionally substituted with one, two or three substituents, identicallyor differently, selected from the group consisting of halogen, hydroxy,cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-,acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁶ and R⁷, independently from each other represent a groupselected from a hydrogen atom, cyano, —C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O)₂R¹⁰,—C(═O)NR⁸R⁹, C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-,

wherein said C₁-C₆-alkyl- or C₃-C₅-cycloalkyl- group is optionallysubstituted with one, two or three substituents, identically ordifferently, selected from the group consisting of halogen, hydroxy,cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-,cyclic amines, fluoro-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁶ and R⁷, independently from each other represent a groupselected from a hydrogen atom, cyano, —C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O)₂R¹⁰,—C(═O)NR⁸R⁹, C₁-C₄-alkyl-,

wherein said C₁-C₄-alkyl- group is optionally substituted with onesubstituent selected from the group consisting of a fluorine atom,hydroxy, cyano, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, cyclicamines.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ and R⁷, independently from each other representa group selected from a hydrogen atom, cyano, C₁-C₄-alkyl-,

wherein said C₁-C₄-alkyl- group is optionally substituted with onehydroxy group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ and R⁷, independently from each other representa group selected from a hydrogen atom, cyano, C₁-C₄-alkyl-,

wherein said C₁-C₄-alkyl- group is optionally substituted with onehydroxy group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ and R⁷, independently from each other representa group selected from a hydrogen atom, cyano, —C(═O)R¹⁰, —C(═O)OR¹⁰,C₁-C₃-alkyl-.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ and R⁷, independently from each other representa group selected from a hydrogen atom and —C(═O)OR¹⁰.

In particularly preferred embodiment the invention relates to compoundsof formula (I), in which R⁶ and R⁷, independently from each otherrepresent a group selected from a hydrogen atom and C₁-C₃-alkyl-.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁶ and R⁷, independently from eachother represent a group selected from a hydrogen atom and a cyano group.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁶ and R⁷, independently from eachother represent a group selected from a hydrogen atom and a methyl-group.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁶ and R⁷ represent a hydrogen atom;

In another embodiment the invention relates to compounds of formula (I),in which R⁶ represents a hydrogen atom and R⁷ represents a groupselected from a hydrogen atom, cyano, —C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O)₂R¹⁰,—C(═O)NR⁸R⁹, C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-,

wherein said C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-group isoptionally substituted with one, two or three substituents, identicallyor differently, selected from the group consisting of halogen, hydroxy,cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-,acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁶ represents a hydrogen atom and R⁷ represents a groupselected from a hydrogen atom, cyano, —C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O)₂R¹⁰,—C(═O)NR⁸R⁹, C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-,

wherein said C₁-C₆-alkyl- or C₃-C₅-cycloalkyl- group is optionallysubstituted with one, two or three substituents, identically ordifferently, selected from the group consisting of halogen, hydroxy,cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-,cyclic amines, fluoro-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁶ represents a hydrogen atom and R⁷ represents a groupselected rom a hydrogen atom, cyano, —C(═O)R¹⁰, —C(═O)OR¹⁰, —S(═O)₂R¹⁰,—C(═O)NR⁸R⁹, C₁-C₄-alkyl-, C₃-C₅-cycloalkyl-,

wherein said C₁-C₄-alkyl- or C₃-C₅-cycloalkyl- group is optionallysubstituted with one substituent selected from the group consisting offluorine, hydroxy, cyano, C₁-C₃-alkoxy-, —NH₂, alkylamino-,dialkylamino-, cyclic amines.

In another preferred embodiment the invention relates to compounds offormula (I in which R⁶ represents a hydrogen atom and R⁷ represents agroup selected from a hydrogen atom, cyano, —C(═O)R¹⁰, —C(═O)OR¹⁰,—S(═O)₂R¹⁰, —C(═O)NR⁸R⁹, C₁-C₄-alkyl-, C₃-C₅-cycloalkyl-,

wherein said C₁-C₄-alkyl- group is optionally substituted with onehydroxy group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ represents a hydrogen atom and R⁷ represents agroup selected from a hydrogen atom, cyano, —C(═O)OR¹⁰, —C(═O)NR⁸R⁹,C₁-C₄-alkyl-, C₃-C₅-cycloalkyl-,

wherein said C₁-C₄-alkyl- group is optionally substituted with onehydroxy group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ represents a hydrogen atom and R⁷ represents agroup selected from a hydrogen atom, cyano, C₁-C₄-alkyl-,C₃-C₅-cycloalkyl-.

In another preferred embodiment the invention relates to compounds offormula (I) in which R⁶ represents a hydrogen atom and R⁷ represents agroup selected from a hydrogen atom, cyano, C₁-C₄-alkyl-.

In a particularly preferred embodiment the invention relates tocompounds of formula (I) in which R⁶ represents a hydrogen atom and R⁷represents a group selected from a hydrogen atom, cyano, C₁-C₃-alkyl-,cyclopropyl-.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁶ represents a hydrogen atom and R⁷represents a group selected from a hydrogen atom, cyano, C₁-C₃-alkyl-.

In another particularly preferred embodiment the invention relates tocompounds of formula (I) in which R⁶ represents a hydrogen atom and R⁷represents a cyano group.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁶ represents a hydrogen atom and R⁷represents a methyl- group.

The invention relates to compounds of formula (I), in which R⁸, R⁹represent, independently from each other, a group selected from ahydrogen atom, C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl-,benzyl- and heteroaryl-,

wherein said C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl-,benzyl- or heteroaryl- group is optionally substituted with one, two orthree substituents, identically or differently, selected from the groupconsisting of halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂,alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, orR⁸ and R⁹, together with the nitrogen atom they are attached to, form acyclic amine.

In another embodiment the invention relates to compounds of formula (I),in which R⁸, R⁹ represent, independently from each other, a groupselected from a hydrogen atom, C₁-C₄-alkyl- and C₃-C₅-cycloalkyl-;

wherein said C₁-C₄-alkyl- or C₃-C₅-cycloalkyl-group is optionallysubstituted with one or two substituents, identically or differently,selected from the group consisting of hydroxy, C₁-C₂-alkyl-,C₁-C₂-alkoxy-, —NH₂, alkylamino-, dialkylamino-, cyclic amines, orR⁸ and R⁹, together with the nitrogen atom they are attached to, form acyclic amine.

In another embodiment the invention relates to compounds of formula (I),in which R⁸, R⁹ represent, independently from each other, a groupselected from a hydrogen atom, C₁-C₄-alkyl- and C₃-C₅-cycloalkyl-, or

R⁸ and R⁹, together with the nitrogen atom they are attached to, form acyclic amine.

In another embodiment the invention relates to compounds of formula (I),in which R⁸, R⁹ represent, independently from each other, a groupselected from a hydrogen atom, C₁-C₂-alkyl.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁸ and R⁹ represent, independentlyfrom each other, a group selected from a hydrogen atom and C₁-C₂-alkyl-.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁸ represents a group selected from ahydrogen atom and C₁-C₂-alkyl-, and in which R⁹ represents a hydrogenatom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁸ represents a group selected from ahydrogen atom and C₁-C₂-alkyl-.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁹ represents a hydrogen atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁸ represents a hydrogen atom, and inwhich R⁹ represents a hydrogen atom.

The invention relates to compounds of formula (I), in which R¹⁰represents a group selected from C₁-C₆-alkyl-, halo-C₁-C₃-alkyl-,C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl-, benzyl- and heteroaryl-,

wherein said group is optionally substituted with one, two or threesubstituents, identically or differently, selected from the groupconsisting of halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂,alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R¹⁰ represents a group selected from C₁-C₆-alkyl-,fluoro-C₁-C₃-alkyl-, C₃-C₅-cycloalkyl-, phenyl- and benzyl-,

wherein said group is optionally substituted with one, two or threesubstituents, identically or differently, selected from the groupconsisting of halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂,alkylamino-, dialkylamino-, cyclic amines, fluoro-C₁-C₂-alkyl-,C₁-C₂-fluoroalkoxy-.

In a preferred embodiment the invention relates to compounds of formula(I), in which R¹⁰ represents a group selected from C₁-C₆-alkyl-,fluoro-C₁-C₃-alkyl-, C₃-C₅-cycloalkyl- and benzyl-,

wherein said group is optionally substituted with one substituentselected from the group consisting of halogen, hydroxy, C₁-C₂-alkyl-,C₁-C₂-alkoxy-, —NH₂.

In another preferred embodiment the invention relates to compounds offormula (I), in which R¹⁰ represents a group selected from C₁-C₄-alkyl-,fluoro-C₁-C₃-alkyl-.

In another preferred embodiment the invention relates to compounds offormula (I), in which R¹⁰ represents a C₁-C₄-alkyl- group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R¹⁰ represents a tert-butyl- group.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R³ represents a fluorine atom, R⁴represents a hydrogen atom and R⁵ represents a hydrogen atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R¹ represents a methyl- group, R³represents a fluorine atom, R⁴ represents a hydrogen atom and R⁵represents a hydrogen atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R¹ represents a methyl- group, R²represents a hydrogen atom, R³ represents a fluorine atom, R⁴ representsa hydrogen atom and R⁵ represents a hydrogen atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R¹ represents a methyl-group, R²represents a hydrogen atom, R³ represents a fluorine atom, R⁴ representsa hydrogen atom, R⁵ represents a hydrogen atom and Z represents ahydrogen atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R¹ represents a methyl- group and R⁵represents a hydrogen atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R¹ represents a methyl- group, R⁵represents a hydrogen atom and Z represents a hydrogen atom.

It is to be understood that the present invention relates to anysub-combination within any embodiment of the present invention ofcompounds of formula (I), supra.

More particularly still, the present invention covers compounds offormula (I) which are disclosed in the Example section of this text,infra.

Very specially preferred are combinations of two or more of theabovementioned preferred embodiments.

The above mentioned definitions of groups and radicals which have beendetailed in general terms or in preferred ranges also apply to the endproducts of the formula (I) and, analogously, to the starting materialsor intermediates required in each case for the preparation.

The present invention further relates to intermediate compounds ofgeneral formula (7)

wherein Z, R¹, R², R³, R⁴ and L are as defined for the compound ofgeneral formula (I) according to the invention,or the enantiomers, diastereomers, salts, solvates or salts of solvatesthereof.

The present invention further relates to intermediate compounds ofgeneral formula (19)

wherein Z, R¹, R², R³, R⁴ and L are as defined for the compound ofgeneral formula (I) according to the invention,or the enantiomers, diastereomers, salts, solvates or salts of solvatesthereof.

The present invention further relates to the use of intermediatecompounds of general formula (7),

wherein Z, R¹, R², R³, R⁴ and L are as defined for the compound ofgeneral formula (I) according to the invention, or the enantiomers,diastereomers, salts, solvates or salts of solvates thereof, for thepreparation of a compound of general formula (I) according to theinvention.

The present invention further relates to the us of intermediatecompounds of general formula (19),

wherein Z, R¹, R², R³, R⁴ and L are as defined for the compound ofgeneral formula (I) according to the invention,or the enantiomers, diastereomers, salts, solvates or salts of solvatesthereof, for the preparation of a compound of general formula (I)according to the invention.

The present invention further relates to a process for the preparationof a compound of formula (Ta), in which process a compound of theformula (7) wherein Z, R¹, R², R³, R⁴ and L are as defined for thecompound of general formula (I) according to the invention,

is reacted in a C—N cross-coupling reaction to give compounds of theformula (Ia),

and in which process the resulting compound is optionally, ifappropriate, converted with the corresponding (i) solvents and/or (ii)bases or acids to the solvates, salts and/or solvates of the saltsthereof.

The present invention further relates to a process for the preparationof a compound of formula (Id), in which process a compound of theformula (19), wherein Z, R¹, R², R³, R⁴ and L are as defined for thecompound of general formula (I) according to the invention,

is reacted in a C—N cross-coupling reaction to give compounds of theformula (Id),

and in which process the resulting compound is optionally, ifappropriate, converted with the corresponding (i) solvents and/or (ii)bases or acids to the solvates, salts and/or solvates of the saltsthereof.

The present invention further relates to a process for the preparationof the compounds of formula (Ta), in which R¹, R², R³, R⁴, Z and L areas defined for the compound of formula (I) according to the invention,in which process compounds of formula (7),

in which R¹, R², R³, R⁴, Z and L are as defined for the compound offormula (I) according to the invention, are reacted in an intramolecularPalladium-catalyzed C—N cross-coupling reaction,

to give compounds of the formula (Ia),and in which process the resulting compounds are optionally, ifappropriate, converted with the corresponding (i) solvents and/or (ii)bases or acids to the solvates, salts and/or solvates of the saltsthereof.

to give compounds of the formula (Tb),

The present invention further relates to a process for the preparationof the compounds of formula (Id), in which R¹, R², R³, R⁴, Z and L areas defined for the compound of formula (I) according to the invention,in which process compounds of formula (19)

in which R¹, R², R³, R⁴, Z and L are as defined for the compound offormula (I) according to the invention, are reacted in an intramolecularPalladium-catalyzed C—N cross-coupling reaction,

to give compounds of the formula (Id),and in which process the resulting compounds are optionally, ifappropriate, converted with the corresponding (i) solvents and/or (ii)bases or acids to the solvates, salts and/or solvates of the saltsthereof.

to give compounds of the formula (Ie),

The compounds according to the invention show a valuable pharmacologicalspectrum of action which could not have been predicted.

They are therefore suitable for use as medicaments for the treatmentand/or prophylaxis of disorders in humans and animals.

The pharmaceutical activity of the compounds according to the inventioncan be explained by their action as selective inhibitors of CDK9, and,more significantly, as selective inhibitors of CDK9 at high ATPconcentrations.

Thus, the compounds according to the general formula (I) as well as theenantiomers, diastereomers, salts, solvates and salts of solvatesthereof are used as selective inhibitors for CDK9.

Furthermore, the compounds according to the invention show aparticularly high potency (demonstrated by a low IC₅₀ value in theCDK9/CycT1 assay) for selectively inhibiting CDK9 activity, inparticular at high ATP concentrations.

In context of the present invention, the IC₅₀ value with respect to CDK9can be determined by the methods described in the method section below.

As compared to many CDK9 inhibitors described in the prior art,compounds of the present invention according to general formula (I) showa surprisingly high potency for inhibiting CDK9 activity, especially athigh ATP concentrations, which is demonstrated by their low IC₅₀ valuein the CDK9/CycT1 high ATP kinase assay. Thus, these compounds have alower probability to be competed out of the ATP-binding pocket ofCDK9/CycT1 kinase due to the high intracellular ATP concentration (R.Copeland et al., Nature Reviews Drug Discovery 2006, 5, 730-739).According to this property the compounds of the present invention areparticularly able to inhibit CDK9/CycT1 within cells for a longer periodof time as compared to classical ATP competitive kinase inhibitors. Thisincreases the anti-tumor cell efficacy at pharmacokineticclearance-mediated declining serum concentrations of the inhibitor afterdosing of a patient or an animal.

As compared to CDK9 inhibitors in the prior art, compounds in thepresent invention show a surprisingly long target residence time. It hasbeen suggested earlier that the target residence time is an appropriatepredictor for drug efficacy on the basis that equilibrium-based in vitroassays inadequately reflect in vivo situations where drug concentrationsfluctuate due to adsorption, distribution and elimination processes andthe target protein concentration may be dynamically regulated (Tummino,P. J. and R. A. Copeland, Residence time of receptor—ligand complexesand its effect on biological function. Biochemistry, 2008. 47(20): p.5481-5492; Copeland, R. A., D. L. Pompliano, and T. D. Meek, Drug-targetresidence time and its implications for lead optimization. NatureReviews Drug Discovery, 2006. 5(9): p. 730-739).

Therefore, the equilibrium binding parameter, K_(D), or the functionalrepresentative, IC₅₀, may not fully reflect requirements for in vivoefficacy. Assuming that a drug molecule can only act as long as itremains bound to its target, the “lifetime” (residence time), of thedrug-target complex may serve as a more reliable predictor for drugefficacy in a non-equilibrium in vivo system. Several publicationsappreciated and discussed its implications for in vivo efficacy (Lu, H.and P. J. Tonge, Drug-target residence time: critical information forlead optimization. Curr Opin Chem Biol, 2010. 14(4): p. 467-74;Vauquelin, G. and S. J. Charlton, Long-lasting target binding andrebinding as mechanisms to prolong in vivo drug action. Br J Pharmacol,2010. 161(3): p. 488-508).

One example for the impact of target residence time is given by the drugtiotropium that is used in COPD treatment. Tiotropium binds to the M1,M2 and M3 subtype of the muscarinic receptors with comparableaffinities, but is kinetically selective as it has the desired longresidence times only for the M3 receptor. Its drug-target residence timeis sufficiently long that after washout from human trachea in vitro,tiotropium maintains inhibition of cholinergic activity with a half-lifeof 9 hours. This translates to protection against bronchospasms for morethan 6 hours in vivo (Price, D., A. Sharma, and F. Cerasoli, Biochemicalproperties, pharmacokinetics and pharmacological response of tiotropiumin chronic obstructive pulmonary disease patients. 2009; Dowling, M.(2006) Br. J. Pharmacol. 148, 927-937).

Another example is Lapatinib (Tykerb). It was found was that the longtarget residence time found for lapatinib in the purified intracellulardomain enzyme reaction correlated with the observed, prolonged signalinhibition in tumor cells based on receptor tyrosine phosphorylationmeasurements. It was subsequently concluded that the slow bindingkinetics may offer increased signal inhibition in the tumor, thusleading to greater potential to affect the tumor growth rates oreffectiveness of co-dosing with other chemotherapeutic agents. (Wood etal (2004) Cancer Res. 64: 6652-6659; Lackey (2006) Current Topics inMedicinal Chemistry, 2006, Vol. 6, No. 5)

In context of the present invention, the IC₅₀ value with respect to CDK9at high ATP concentrations can be determined by the methods described inthe method section below. Preferably, it is determined according toMethod 1b (“CDK9/CycT1 high ATP kinase assay”) as described in theMaterials and Method section below.

If desired, the IC₅₀ value with respect to CDK9 at low ATP concentrationcan e.g. be determined by the methods described in the method sectionbelow, according to Method 1a. (“CDK9/CycT1 kinase assay”) described inthe Materials and Method section below.

In context of the present invention, the target residence time ofselective CDK9 inhibitors according to the present invention can bedetermined by the methods described in the method section below.Preferably, it is determined according to Method 8 (“Surface PlasmonResonance PTEFb”) as described in the Materials and Method sectionbelow.

Further, compounds of the present invention according to formula (I)surprisingly show a surprisingly high anti-proliferative activity intumor cell lines, such as HeLa, HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2,B16F10, A2780 or MOLM-13, compared to CDK9 inhibitors described in theprior art.

In context of the present invention, the anti-proliferative activity intumor cell lines such as HeLa, HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2,B16F10, A2780 or MOLM-13 is preferably determined according to Method 3.(“Proliferation Assay”) as described in the Materials and Method sectionbelow.

In context of the present invention, the aqueous solubility ispreferably determined according to Method 4. (“Equilibrium Shake FlaskSolubility Assay”) described in the Materials and Method section below.

In context of the present invention, the metabolic stability in rathepatocytes is preferably determined according to Method 6.(“Investigation of in vitro metabolic stability in rat hepatocytes”)described in the Materials and Method section below.

In context of the present invention, the half-life in rats uponadministration in vivo is preferably determined according to Method 7.(“In vivo pharmacokinetics in rats”) described in the Materials andMethod section below.

In context of the present invention, the apparent Caco-2 permeabilityvalues from the basal to apical compartment (P_(app) A−B) or the effluxratio (defined as the ratio ((P_(app) B−A)/(P_(app) A−B)) are preferablydetermined according to Method 5. (“Caco-2 Permeation Assay”) describedin the Materials and Method section below.

A further subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention for thetreatment and/or prophylaxis of disorders, preferably of disordersrelating to or mediated by CDK9 activity, in particular ofhyper-proliferative disorders, virally induced infectious diseasesand/or of cardiovascular diseases, more preferably ofhyper-proliferative disorders.

The compounds of the present invention may be used to inhibitselectively the activity or expression of CDK9.

Therefore, the compounds of formula (I) are expected to be valuable astherapeutic agents. Accordingly, in another embodiment, the presentinvention provides a method of treating disorders relating to ormediated by CDK9 activity in a patient in need of such treatment,comprising administering to the patient an effective amount of acompound of formula (I) as defined above. In certain embodiments, thedisorders relating to CDK9 activity are hyper-proliferative disorders,virally induced infectious diseases and/or of cardiovascular diseases,more preferably hyper-proliferative disorders, particularly cancer.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of a disease or disorder, such as a carcinoma.

The term “subject” or “patient” includes organisms which are capable ofsuffering from a cell proliferative disorder or a disorder associatedwith reduced or insufficient programmed cell death (apoptosis) or whocould otherwise benefit from the administration of a compound of theinvention, such as human and non-human animals. Preferred humans includehuman patients suffering from or prone to suffering from a cellproliferative disorder or associated state, as described herein. Theterm “non-human animals” includes vertebrates, e.g., mammals, such asnon-human primates, sheep, cow, dog, cat and rodents, e.g., mice, andnon-mammals, such as chickens, amphibians, reptiles, etc.

The term “disorders relating to or mediated by CDK9” shall includediseases associated with or implicating CDK9 activity, for example thehyperactivity of CDK9, and conditions that accompany with thesediseases. Examples of “disorders relating to or mediated by CDK9”include disorders resulting from increased CDK9 activity due tomutations in genes regulating CDK9 activity such as LARP7, HEXIM1/2 or7sk snRNA, or disorders resulting from increased CDK9 activity due toactivation of the CDK9/cyclinT/RNApolymerase II complex by viralproteins such as HIV-TAT or HTLV-TAX or disorders resulting fromincreased CDK9 activity due to activation of mitogenic signalingpathways.

The term “hyperactivity of CDK9” refers to increased enzymatic activityof CDK9 as compared to normal non-diseased cells, or it refers toincreased CDK9 activity leading to unwanted cell proliferation, or toreduced or insufficient programmed cell death (apoptosis), or mutationsleading to constitutive activation of CDK9.

The term “hyper-proliferative disorder” includes disorders involving theundesired or uncontrolled proliferation of a cell and it includesdisorders involving reduced or insufficient programmed cell death(apoptosis). The compounds of the present invention can be utilized toprevent, inhibit, block, reduce, decrease, control, etc., cellproliferation and/or cell division, and/or produce apoptosis. Thismethod comprises administering to a subject in need thereof, including amammal, including a human, an amount of a compound of this invention, ora pharmaceutically acceptable salt, hydrate or solvate thereof which iseffective to treat or prevent the disorder.

Hyper-proliferative disorders in the context of this invention include,but are not limited to, e.g., psoriasis, keloids and other hyperplasiasaffecting the skin, endometriosis, skeletal disorders, angiogenic orblood vessel proliferative disorders, pulmonary hypertension, fibroticdisorders, mesangial cell proliferative disorders, colonic polyps,polycystic kidney disease, benign prostate hyperplasia (BPH), and solidtumors, such as cancers of the breast, respiratory tract, brain,reproductive organs, digestive tract, urinary tract, eye, liver, skin,head and neck, thyroid, parathyroid, and their distant metastases. Thosedisorders also include lymphomas, sarcomas and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ, and canine or feline mammary carcinoma.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma, pleuropulmonary blastoma, and mesothelioma.

Examples of brain cancers include, but are not limited to brain stem andhypothalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer.

Tumors of the female reproductive organs include, but are not limited toendometrial, cervical, ovarian, vaginal and vulvar cancer, as well assarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, salivary gland cancers, anal gland adenocarcinomas, andmast cell tumors.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral, and hereditary andsporadic papillary renal cancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer,non-melanoma skin cancer, and mast cell tumors.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer, squamous cell cancer, and oral melanoma.

Lymphomas include, but are not limited to AIDS-related lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma,Hodgkin's disease, and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma,rhabdomyosarcoma, malignant histiocytosis, fibrosarcoma,hemangiosarcoma, hemangiopericytoma, and leiomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

Fibrotic proliferative disorders, i.e. the abnormal formation ofextracellular matrices, that may be treated with the compounds andmethods of the present invention include lung fibrosis, atherosclerosis,restenosis, hepatic cirrhosis, and mesangial cell proliferativedisorders, including renal diseases such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic microangiopathysyn-dromes, transplant rejection, and glomerulopathies.

Other conditions in humans or other mammals that may be treated byadministering a compound of the present invention include tumor growth,retinopathy, including diabetic retinopathy, ischemic retinal-veinocclusion, retinopathy of prematurity and age-related maculardegeneration, rheumatoid arthritis, psoriasis, and bullous disordersassociated with subepidermal blister formation, including bullouspemphigoid, erythema multiforme and dermatitis herpetiformis.

The compounds of the present invention may also be used to prevent andtreat diseases of the airways and the lung, diseases of thegastrointestinal tract as well as diseases of the bladder and bile duct.

The disorders mentioned above have been well characterized in humans,but also exist with a similar etiology in other animals, includingmammals, and can be treated by administering pharmaceutical compositionsof the present invention.

In a further aspect of the present invention, the compounds according tothe invention are used in a method for preventing and/or treatinginfectious diseases, in particular virally induced infectious diseases.The virally induced infectious diseases, including opportunisticdiseases, are caused by retroviruses, hepadnaviruses, herpesviruses,flaviviridae, and/or adenoviruses. In a further preferred embodiment ofthis method, the retroviruses are selected from lentiviruses oroncoretroviruses, wherein the lentivirus is selected from the groupcomprising: HIV-1, HIV-2, FIV, BIV, SIVs, SHIV, CAEV, VMV or EIAV,preferably HIV-1 or HIV-2 and wherein the oncoretrovirus is selectedfrom the group of: HTLV-I, HTLV-II or BLV. In a further preferredembodiment of this method, the hepadnavirus is selected from HBV, GSHVor WHV, preferably HBV, the herpesvirus is selected from the groupcomprising: HSV I, HSV II, EBV, VZV, HCMV or HHV 8, preferably HCMV andthe flaviviridae is selected from HCV, West nile or Yellow Fever.

The compounds according to general formula (I) are also useful forprophylaxis and/or treatment of cardiovascular diseases such as cardiachypertrophy, adult congenital heart disease, aneurysm, stable angina,unstable angina, angina pectoris, angioneurotic edema, aortic valvestenosis, aortic aneurysm, arrhythmia, arrhythmogenic right ventriculardysplasia, arteriosclerosis, arteriovenous malformations, atrialfibrillation, Behcet syndrome, bradycardia, cardiac tamponade,cardiomegaly, congestive cardiomyopathy, hypertrophic cardiomyopathy,restrictive cardiomyopathy, cardiovascular disease prevention, carotidstenosis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes,Ebstein's Anomaly, Eisenmenger complex, cholesterol embolism, bacterialendocarditis, fibromuscular dysplasia, congenital heart defects, heartdiseases, congestive heart failure, heart valve diseases, heart attack,epidural hematoma, hematoma, subdural, Hippel-Lindau disease, hyperemia,hypertension, pulmonary hypertension, hypertrophic growth, leftventricular hypertrophy, right ventricular hypertrophy, hypoplastic leftheart syndrome, hypotension, intermittent claudication, ischemic heartdisease, Klippel-Trenaunay-Weber syndrome, lateral medullary syndrome,long QT syndrome mitral valve prolapse, moyamoya disease, mucocutaneouslymph node syndrome, myocardial infarction, myocardial ischemia,myocarditis, pericarditis, peripheral vascular diseases, phlebitis,polyarteritis nodosa, pulmonary atresia, Raynaud disease, restenosis,Sneddon syndrome, stenosis, superior vena cava syndrome, syndrome X,tachycardia, Takayasu's arteritis, hereditary hemorrhagictelangiectasia, telangiectasis, temporal arteritis, tetralogy of fallot,thromboangiitis obliterans, thrombosis, thromboembolism, tricuspidatresia, varicose veins, vascular diseases, vasculitis, vasospasm,ventricular fibrillation, Williams syndrome, peripheral vasculardisease, varicose veins and leg ulcers, deep vein thrombosis,Wolff-Parkinson-White syndrome.

Preferred are cardiac hypertrophy, adult congenital heart disease,aneurysms, angina, angina pectoris, arrhythmias, cardiovascular diseaseprevention, cardiomyopathies, congestive heart failure, myocardialinfarction, pulmonary hypertension, hypertrophic growth, restenosis,stenosis, thrombosis and arteriosclerosis.

A further subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention as amedicament.

A further subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention for thetreatment and/or prophylaxis of disorders, in particular of thedisorders mentioned above.

A further subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention for thetreatment and/or prophylaxis of hyper-proliferative disorders, virallyinduced infectious diseases and/or of cardiovascular diseases.

A preferred subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention for thetreatment and/or prophylaxis of lung carcinomas, especially non-smallcell lung carcinomas, prostate carcinomas, especiallyhormone-independent human prostate carcinomas, cervical carcinomas,including multidrug-resistant human cervical carcinomas, colorectalcarcinomas, melanomas, ovarian carcinomas or leukemias, especially acutemyeloid leukemias.

A further subject matter of the present invention are the compounds ofgeneral formula (I) according to the invention for the use as amedicament.

A further subject matter of the present invention are the compounds ofgeneral formula (I) according to the invention for the use of treatingand/or prophylaxis of the disorders mentioned above.

A further subject matter of the present invention are the compounds ofgeneral formula (I) according to the invention for the use of treatingand/or prophylaxis of hyper-proliferative disorders, virally inducedinfectious diseases and/or of cardiovascular diseases.

A preferred subject matter of the present invention are the compounds ofgeneral formula (I) according to the invention for the use of treatingand/or prophylaxis of lung carcinomas, especially non-small cell lungcarcinomas, prostate carcinomas, especially hormone-independent humanprostate carcinomas, cervical carcinomas, including multidrug-resistanthuman cervical carcinomas, colorectal carcinomas, melanomas, ovariancarcinomas or leukemias, especially acute myeloid leukemias.

A further subject matter of the present invention are the compounds ofgeneral formula (I) according to the invention for the use in a methodfor the treatment and/or prophylaxis of the disorders mentioned above.

A further subject matter of the present invention are the compounds ofgeneral formula (I) according to the invention for the use in a methodfor the treatment and/or prophylaxis of hyper-proliferative disorders,virally induced infectious diseases and/or of cardiovascular diseases.

A preferred subject matter of the present invention are the compounds ofgeneral formula (I) according to the invention for the use in a methodof treatment and/or prophylaxis of lung carcinomas, especially non-smallcell lung carcinomas, prostate carcinomas, especiallyhormone-independent human prostate carcinomas, cervical carcinomas,including multidrug-resistant human cervical carcinomas, colorectalcarcinomas, melanomas, ovarian carcinomas or leukemias, especially acutemyeloid leukemias.

A further subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention in themanufacture of a medicament for the treatment and/or prophylaxis ofdisorders, in particular the disorders mentioned above.

A further subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention in themanufacture of a medicament for the treatment and/or prophylaxis ofhyper-proliferative disorders, virally induced infectious diseasesand/or of cardiovascular diseases.

A preferred subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention in themanufacture of a medicament for the treatment and/or prophylaxis of lungcarcinomas, especially non-small cell lung carcinomas, prostatecarcinomas, especially hormone-independent human prostate carcinomas,cervical carcinomas, including multidrug-resistant human cervicalcarcinomas, colorectal carcinomas, melanomas, ovarian carcinomas orleukemias, especially acute myeloid leukemias.

A further subject matter of the present invention is a method for thetreatment and/or prophylaxis of disorders, in particular the disordersmentioned above, using an effective amount of the compounds of generalformula (I) according to the invention.

A further subject matter of the present invention is a method for thetreatment and/or prophylaxis of hyper-proliferative disorders, virallyinduced infectious diseases and/or of cardiovascular diseases, using aneffective amount of the compounds of general formula (I) according tothe invention.

A preferred subject matter of the present invention is a method for thetreatment and/or prophylaxis of lung carcinomas, especially non-smallcell lung carcinomas, prostate carcinomas, especiallyhormone-independent human prostate carcinomas, cervical carcinomas,including multidrug-resistant human cervical carcinomas, colorectalcarcinomas, melanomas, ovarian carcinomas or leukemias, especially acutemyeloid leukemias using an effective amount of the compounds of generalformula (I) according to the invention.

Another aspect of the present invention relates to pharmaceuticalcombinations comprising a compound of general formula (I) according tothe invention in combination with at least one or more further activeingredients.

As used herein the term “pharmaceutical combination” refers to acombination of at least one compound of general formula (I) according tothe invention as active ingredient together with at least one otheractive ingredient with or without further ingredients, carrier, diluentsand/or solvents.

Another aspect of the present invention relates to pharmaceuticalcompositions comprising a compound of general formula (I) according tothe invention in combination with an inert, nontoxic, pharmaceuticallysuitable adjuvant.

As used herein the term “pharmaceutical composition” refers to a galenicformulation of at least one pharmaceutically active agent together withat least one further ingredient, carrier, diluent and/or solvent.

Another aspect of the present invention relates to the use of thepharmaceutical combinations and/or the pharmaceutical compositionsaccording to the invention for the treatment and/or prophylaxis ofdisorders, in particular of the disorders mentioned above.

Another aspect of the present invention relates to the use of thepharmaceutical combinations and/or the pharmaceutical compositionsaccording to the invention for the treatment and/or prophylaxis of lungcarcinomas, especially non-small cell lung carcinomas, prostatecarcinomas, especially hormone-independent human prostate carcinomas,cervical carcinomas, including multidrug-resistant human cervicalcarcinomas, colorectal carcinomas, melanomas, ovarian carcinomas orleukemias, especially acute myeloid leukemias.

Another aspect of the present invention relates to pharmaceuticalcombinations and/or the pharmaceutical compositions according to theinvention for use of the treatment and/or prophylaxis of disorders, inparticular of the disorders mentioned above.

Another aspect of the present invention relates to pharmaceuticalcombinations and/or the pharmaceutical compositions according to theinvention for use of the treatment and/or prophylaxis of lungcarcinomas, especially non-small cell lung carcinomas, prostatecarcinomas, especially hormone-independent human prostate carcinomas,cervical carcinomas, including multidrug-resistant human cervicalcarcinomas, colorectal carcinomas, melanomas, ovarian carcinomas orleukemias, especially acute myeloid leukemias.

Compounds of formula (I) may be administered as the sole pharmaceuticalagent or in combination with one or more additional therapeutic agentswhere the combination causes no unacceptable adverse effects.

This pharmaceutical combination includes administration of a singlepharmaceutical dosage formulation which contains a compound of formula(I) and one or more additional therapeutic agents, as well asadministration of the compound of formula (I) and each additionaltherapeutic agent in its own separate pharmaceutical dosage formulation.For example, a compound of formula (I) and a therapeutic agent may beadministered to the patient together in a single oral dosage compositionsuch as a tablet or capsule, or each agent may be administered inseparate dosage formulations.

Where separate dosage formulations are used, the compound of formula (I)and one or more additional therapeutic agents may be administered atessentially the same time (e.g., concurrently) or at separatelystaggered times (e.g., sequentially).

In particular, the compounds of the present invention may be used infixed or separate combination with other anti-tumor agents such asalkylating agents, anti-metabolites, plant-derived anti-tumor agents,hormonal therapy agents, topoisomerase inhibitors, camptothecinderivatives, kinase inhibitors, targeted drugs, antibodies, interferonsand/or biological response modifiers, anti-angiogenic compounds, andother anti-tumor drugs. In this regard, the following is a non-limitinglist of examples of secondary agents that may be used in combinationwith the compounds of the present invention:

-   -   Alkylating agents include, but are not limited to, nitrogen        mustard N-oxide, cyclophosphamide, ifosfamide, thiotepa,        ranimustine, nimustine, temozolomide, altretamine, apaziquone,        brostallicin, bendamustine, carmustine, estramustine,        fotemustine, glufosfamide, mafosfamide, bendamustin, and        mitolactol; platinum-coordinated alkylating compounds include,        but are not limited to, cisplatin, carboplatin, eptaplatin,        lobaplatin, nedaplatin, oxaliplatin, and satraplatin;    -   Anti-metabolites include, but are not limited to, methotrexate,        6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil alone        or in combination with leucovorin, tegafur, doxifluridine,        carmofur, cytarabine, cytarabine ocfosfate, enocitabine,        gemcitabine, fludarabin, 5-azacitidine, capecitabine,        cladribine, clofarabine, decitabine, eflornithine,        ethynylcytidine, cytosine arabinoside, hydroxyurea, melphalan,        nelarabine, nolatrexed, ocfosfite, disodium premetrexed,        pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate,        vidarabine, vincristine, and vinorelbine;    -   Hormonal therapy agents include, but are not limited to,        exemestane, Lupron, anastrozole, doxercalciferol, fadrozole,        formestane, 11-beta hydroxysteroid dehydrogenase 1 inhibitors,        17-alpha hydroxylase/17,20 lyase inhibitors such as abiraterone        acetate, 5-alpha reductase inhibitors such as finasteride and        epristeride, anti-estrogens such as tamoxifen citrate and        fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene,        letrozole, anti-androgens such as bicalutamide, flutamide,        mifepristone, nilutamide, Casodex, and anti-progesterones and        combinations thereof;    -   Plant-derived anti-tumor substances include, e.g., those        selected from mitotic inhibitors, for example epothilones such        as sagopilone, ixabepilone and epothilone B, vinblastine,        vinflunine, docetaxel, and paclitaxel;    -   Cytotoxic topoisomerase inhibiting agents include, but are not        limited to, aclarubicin, doxorubicin, amonafide, belotecan,        camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin,        diflomotecan, irinotecan, topotecan, edotecarin, epimbicin,        etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone,        pirambicin, pixantrone, rubitecan, sobuzoxane, tafluposide, and        combinations thereof;    -   Immunologicals include interferons such as interferon alpha,        interferon alpha-2a, interferon alpha-2b, interferon beta,        interferon gamma-1a and interferon gamma-ni, and other immune        enhancing agents such as L19-IL2 and other IL2 derivatives,        filgrastim, lentinan, sizofilan, TheraCys, ubenimex,        aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab,        denileukin, gemtuzumab, ozogamicin, ibritumomab, imiquimod,        lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim,        sargramostim, tasonermin, tecleukin, thymalasin, tositumomab,        Vimlizin, epratuzumab, mitumomab, oregovomab, pemtumomab, and        Provenge; Merial melanoma vaccine    -   Biological response modifiers are agents that modify defense        mechanisms of living organisms or biological responses such as        survival, growth or differentiation of tissue cells to direct        them to have anti-tumor activity; such agents include, e.g.,        krestin, lentinan, sizofiran, picibanil, ProMune, and ubenimex;    -   Anti-angiogenic compounds include, but are not limited to,        acitretin, aflibercept, angiostatin, aplidine, asentar,        axitinib, recentin, bevacizumab, brivanib alaninat, cilengtide,        combretastatin, DAST, endostatin, fenretinide, halofuginone,        pazopanib, ranibizumab, rebimastat, removab, revlimid,        sorafenib, vatalanib, squalamine, sunitinib, telatinib,        thalidomide, ukrain, and vitaxin;    -   Antibodies include, but are not limited to, trastuzumab,        cetuximab, bevacizumab, rituximab, ticilimumab, ipilimumab,        lumiliximab, catumaxomab, atacicept, oregovomab, and        alemtuzumab;    -   VEGF inhibitors such as, e.g., sorafenib, DAST, bevacizumab,        sunitinib, recentin, axitinib, aflibercept, telatinib, brivanib        alaninate, vatalanib, pazopanib, and ranibizumab; Palladia    -   EGFR (HER1) inhibitors such as, e.g., cetuximab, panitumumab,        vectibix, gefitinib, erlotinib, and Zactima;    -   HER2 inhibitors such as, e.g., lapatinib, trastuzumab, and        pertuzumab;    -   mTOR inhibitors such as, e.g., temsirolimus,        sirolimus/Rapamycin, and everolimus;    -   c-Met inhibitors;    -   PI3K and AKT inhibitors;    -   CDK inhibitors such as roscovitine and flavopiridol;    -   Spindle assembly checkpoints inhibitors and targeted        anti-mitotic agents such as PLK inhibitors, Aurora inhibitors        (e.g. Hesperadin), checkpoint kinase inhibitors, and KSP        inhibitors;    -   HDAC inhibitors such as, e.g., panobinostat, vorinostat, MS275,        belinostat, and LBH589;    -   HSP90 and HSP70 inhibitors;    -   Proteasome inhibitors such as bortezomib and carfilzomib;    -   Serine/threonine kinase inhibitors including MEK inhibitors        (such as e.g. RDEA 119) and Raf inhibitors such as sorafenib;    -   Farnesyl transferase inhibitors such as, e.g., tipifarnib;    -   Tyrosine kinase inhibitors including, e.g., dasatinib,        nilotibib, DAST, bosutinib, sorafenib, bevacizumab, sunitinib,        AZD2171, axitinib, aflibercept, telatinib, imatinib mesylate,        brivanib alaninate, pazopanib, ranibizumab, vatalanib,        cetuximab, panitumumab, vectibix, gefitinib, erlotinib,        lapatinib, tratuzumab, pertuzumab, and c-Kit inhibitors;        Palladia, masitinib    -   Vitamin D receptor agonists;    -   Bcl-2 protein inhibitors such as obatoclax, oblimersen sodium,        and gossypol;    -   Cluster of differentiation 20 receptor antagonists such as,        e.g., rituximab;    -   Ribonucleotide reductase inhibitors such as, e.g., gemcitabine;    -   Tumor necrosis apoptosis inducing ligand receptor 1 agonists        such as, e.g., mapatumumab;    -   5-Hydroxytryptamine receptor antagonists such as, e.g., rEV598,        xaliprode, palonosetron hydrochloride, granisetron, Zindol, and        AB-1001;    -   Integrin inhibitors including alpha5-beta1 integrin inhibitors        such as, e.g., E7820, JSM 6425, volociximab, and endostatin;    -   Androgen receptor antagonists including, e.g., nandrolone        decanoate, fluoxymesterone, Android, Prost-aid, andromustine,        bicalutamide, flutamide, apo-cyproterone, apo-flutamide,        chlormadinone acetate, Androcur, Tabi, cyproterone acetate, and        nilutamide;    -   Aromatase inhibitors such as, e.g., anastrozole, letrozole,        testolactone, exemestane, amino-glutethimide, and formestane;    -   Matrix metalloproteinase inhibitors;    -   Other anti-cancer agents including, e.g., alitretinoin,        ampligen, atrasentan bexarotene, bortezomib, bosentan,        calcitriol, exisulind, fotemustine, ibandronic acid,        miltefosine, mitoxantrone, I-asparaginase, procarbazine,        dacarbazine, hydroxycarbamide, pegaspargase, pentostatin,        tazaroten, velcade, gallium nitrate, canfosfamide, darinaparsin,        and tretinoin.

The compounds of the present invention may also be employed in cancertreatment in conjunction with radiation therapy and/or surgicalintervention.

Generally, the use of cytotoxic and/or cytostatic agents in combinationwith a compound or composition of the present invention will serve to:

-   (1) yield better efficacy in reducing the growth of a tumor or even    eliminate the tumor as compared to administration of either agent    alone,-   (2) provide for the administration of lesser amounts of the    administered chemotherapeutic agents,-   (3) provide for a chemotherapeutic treatment that is well tolerated    in the patient with fewer deleterious pharmacological complications    than observed with single agent chemotherapies and certain other    combined therapies,-   (4) provide for treating a broader spectrum of different cancer    types in mammals, especially humans,-   (5) provide for a higher response rate among treated patients,-   (6) provide for a longer survival time among treated patients    compared to standard chemotherapy treatments,-   (7) provide a longer time for tumor progression, and/or-   (8) yield efficacy and tolerability results at least as good as    those of the agents used alone, compared to known instances where    other cancer agent combinations produce antagonistic effects.

Furthermore, the compounds of formula (I) may be utilized, as such or incompositions, in research and diagnostics, or as analytical referencestandards, and the like, which are well known in the art.

The compounds according to the invention can act systemically and/orlocally. For this purpose, they can be administered in a suitable way,such as, for example, by the oral, parenteral, pulmonal, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivalor otic route, or as an implant or stent.

For these administration routes, it is possible to administer thecompounds according to the invention in suitable application forms.

Suitable for oral administration are administration forms which work asdescribed in the prior art and deliver the compounds according to theinvention rapidly and/or in modified form, which comprise the compoundsaccording to the invention in crystalline and/or amorphous and/ordissolved form, such as, for example, tablets (coated or uncoated, forexample tablets provided with enteric coatings or coatings whosedissolution is delayed or which are insoluble and which control therelease of the compound according to the invention), tablets whichrapidly decompose in the oral cavity, or films/wafers,films/lyophilizates, capsules (for example hard or soft gelatincapsules), sugar-coated tablets, granules, pellets, powders, emulsions,suspensions, aerosols or solutions.

Parenteral administration can take place with avoidance of an absorptionstep (for example intravenously, intraarterially, intracardially,intraspinally or intralumbally) or with inclusion of absorption (forexample intramuscularly, subcutaneously, intracutaneously,percutaneously or intraperitoneally). Administration forms suitable forparenteral administration are, inter alia, preparations for injectionand infusion in the form of solutions, suspensions, emulsions,lyophilizates or sterile powders.

Examples suitable for the other administration routes are pharmaceuticalforms for inhalation (inter alia powder inhalers, nebulizers), nasaldrops/solutions/sprays; tablets to be administered lingually,sublingually or buccally, films/wafers or capsules, suppositories,preparations for the eyes or ears, vaginal capsules, aqueous suspensions(lotions, shaking mixtures), lipophilic suspensions, ointments, creams,transdermal therapeutic systems (such as plasters, for example), milk,pastes, foams, dusting powders, implants or stents.

The compounds according to the invention can be converted into thestated administration forms. This can take place in a manner known perse by mixing with inert, nontoxic, pharmaceutically suitable adjuvants.These adjuvants include, inter alia, carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (for exampleliquid polyethylene glycols), emulsifiers and dispersants or wettingagents (for example sodium dodecyl sulphate, polyoxysorbitan oleate),binders (for example polyvinylpyrrolidone), synthetic and naturalpolymers (for example albumin), stabilizers (for example antioxidants,such as, for example, ascorbic acid), colorants (for example inorganicpigments, such as, for example, iron oxides) and flavour- and/orodour-masking agents.

The present invention furthermore provides medicaments comprising atleast one compound according to the invention, usually together with oneor more inert, nontoxic, pharmaceutically suitable adjuvants, and theiruse for the purposes mentioned above.

When the compounds of the present invention are administered aspharmaceuticals, to humans or animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1% to 99.5% (morepreferably 0.5% to 90%) of active ingredient in combination with one ormore inert, nontoxic, pharmaceutically suitable adjuvants.

Regardless of the route of administration selected, the compoundsaccording to the invention of general formula (I) and/or thepharmaceutical composition of the present invention are formulated intopharmaceutically acceptable dosage forms by conventional methods knownto those of skill in the art.

Actual dosage levels and time course of administration of the activeingredients in the pharmaceutical compositions of the invention may bevaried so as to obtain an amount of the active ingredient which iseffective to achieve the desired therapeutic response for a particularpatient without being toxic to the patient.

Materials and Methods:

The percentage data in the following tests and examples are percentagesby weight unless otherwise indicated; parts are parts by weight. Solventratios, dilution ratios and concentration data of liquid/liquidsolutions are in each case based on volume.

Examples were tested in selected biological and/or physicochemicalassays one or more times. When tested more than once, data are reportedas either average values or as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological and/or physicochemical assays representaverage values or median values calculated utilizing data sets obtainedfrom testing of one or more synthetic batch.

The in vitro pharmacological, pharmacokinetic and physicochemicalproperties of the compounds can be determined according to the followingassays and methods.

Noteworthily, in the CDK9 assays described below the resolution power islimited by the enzyme concentrations, the lower limit for IC₅₀s is about1-2 nM in the CDK9 high ATP assay and 2-4 nM in the CDK low ATP assays.For compounds exhibiting IC₅₀s in this range the true affinity to CDK9and thus the selectivity for CDK9 over CDK2 might be even higher, i.e.for these compounds the selectivity factors calculated in columns 4 and7 of Table 2, infra, are minimal values, they could be also higher.

1a. CDK9/CycT1 Kinase Assay

CDK9/CycT1-inhibitory activity of compounds of the present invention wasquantified employing the CDK9/CycT1 TR-FRET assay as described in thefollowing paragraphs.

Recombinant full-length His-tagged human CDK9 and CycT1, expressed ininsect cells and purified by Ni-NTA affinity chromatography, werepurchase from Invitrogen (Cat. No PV4131). As substrate for the kinasereaction biotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus inamid form) was used which can be purchased e.g. form the company JERINIpeptide technologies (Berlin, Germany). For the assay 50 nl of a 100foldconcentrated solution of the test compound in DMSO was pipetted into ablack low volume 384well microtiter plate (Greiner Bio-One,Frickenhausen, Germany), 2 μl of a solution of CDK9/CycT1 in aqueousassay buffer [50 mM Tris/HCl pH 8.0, 10 mM MgCl2, 1.0 mM dithiothreitol,0.1 mM sodium ortho-vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)] wereadded and the mixture was incubated for 15 min at 22° C. to allowpre-binding of the test compounds to the enzyme before the start of thekinase reaction. Then the kinase reaction was started by the addition of3 μl of a solution of adenosine-tri-phosphate (ATP, 16.7 μM=>final conc.in the 5 μl assay volume is 10 μM) and substrate (1.25 μM=>final conc.in the 5 μl assay volume is 0.75 μM) in assay buffer and the resultingmixture was incubated for a reaction time of 25 min at 22° C. Theconcentration of CDK9/CycT1 was adjusted depending of the activity ofthe enzyme lot and was chosen appropriate to have the assay in thelinear range, typical concentrations were in the range of 1 μg/ml. Thereaction was stopped by the addition of 5 μl of a solution of TR-FRETdetection reagents (0.2 μM streptavidine-XL665 [Cisbio Bioassays,Codolet, France] and 1 nM anti-RB(pSer807/pSer811)-antibody from BDPharmingen [#558389] and 1.2 nM LANCE EU-W1024 labeled anti-mouse IgGantibody [Perkin-Elmer, product no. AD0077]) in an aqueous EDTA-solution(100 mM EDTA, 0.2% (w/v) bovine serum albumin in 100 mM HEPES pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the formationof complex between the phosphorylated biotinylated peptide and thedetection reagents. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theEu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm was measuredin a TR-FRET reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.07 nM (20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 11 nM,3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, the dilution series preparedseparately before the assay on the level of the 100fold concentratedsolutions in DMSO by serial dilutions, exact concentrations may varydepending pipettors used) in duplicate values for each concentration andIC50 values were calculated using Genedata Screener™ software.

1b. CDK9/CycT1 High ATP Kinase Assay

CDK9/CycT1-inhibitory activity of compounds of the present invention ata high ATP concentration after preincubation of enzyme and testcompounds was quantified employing the CDK9/CycT1 TR-FRET assay asdescribed in the following paragraphs.

Recombinant full-length His-tagged human CDK9 and CycT1, expressed ininsect cells and purified by Ni-NTA affinity chromatography, werepurchased from Life Technologies (Cat. No PV4131). As substrate for thekinase reaction biotinylated peptide biotin-Ttds-YISPLKSPYKISEG(C-terminus in amide form) was used which can be purchased e.g. form thecompany JERINI peptide technologies (Berlin, Germany).

For the assay 50 nl of a 100fold concentrated solution of the testcompound in DMSO was pipetted into either a black low volume 384wellmicrotiter plate or a black 1536well microtiter plate (both GreinerBio-One, Frickenhausen, Germany), 2 μl of a solution of CDK9/CycT1 inaqueous assay buffer [50 mM Tris/HCl pH 8.0, 10 mM MgCl2, 1.0 mMdithiothreitol, 0.1 mM sodium ortho-vanadate, 0.01% (v/v) Nonidet-P40(Sigma)] were added and the mixture was incubated for 15 min at 22° C.to allow pre-binding of the test compounds to the enzyme before thestart of the kinase reaction. Then the kinase reaction was started bythe addition of 3 μl of a solution of adenosine-tri-phosphate (ATP, 3.3mM=>final conc. in the 5 μl assay volume is 2 mM) and substrate (1.25μM=>final conc. in the 5 μl assay volume is 0.75 μM) in assay buffer andthe resulting mixture was incubated for a reaction time of 25 min at 22°C. The concentration of CDK9/CycT1 was adjusted depending of theactivity of the enzyme lot and was chosen appropriate to have the assayin the linear range, typical concentrations were in the range of 0.5μg/ml. The reaction was stopped by the addition of 3 μl of a solution ofTR-FRET detection reagents (0.33 μM streptavidine-XL665 [CisbioBioassays, Codolet, France] and 1.67 nManti-RB(pSer807/pSer811)-antibody from BD Pharmingen [#558389] and 2 nMLANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, productno. AD0077]) in an aqueous EDTA-solution (167 mM EDTA, 0.2% (w/v) bovineserum albumin in 100 mM HEPES pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the formationof complex between the phosphorylated biotinylated peptide and thedetection reagents. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theEu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm was measuredin a TR-FRET reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.07 nM (20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 11 nM,3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, the dilution series preparedseparately before the assay on the level of the 100fold concentratedsolutions in DMSO by serial dilutions, exact concentrations may varydepending pipettors used) in duplicate values for each concentration andIC50 values were calculated using Genedata Screener™ software.

2a. CDK2/CycE Kinase Assay

CDK2/CycE-inhibitory activity of compounds of the present invention wasquantified employing the CDK2/CycE TR-FRET assay as described in thefollowing paragraphs.

Recombinant fusion proteins of GST and human CDK2 and of GST and humanCycE, expressed in insect cells (Sf9) and purified byGlutathion-Sepharose affinity chromatography, were purchase fromProQinase GmbH (Freiburg, Germany). As substrate for the kinase reactionbiotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus in amidform) was used which can be purchased e.g. form the company JERINIpeptide technologies (Berlin, Germany).

For the assay 50 nl of a 100fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384well microtiterplate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of a solution ofCDK2/CycE in aqueous assay buffer [50 mM Tris/HCl pH 8.0, 10 mM MgCl2,1.0 mM dithiothreitol, 0.1 mM sodium ortho-vanadate, 0.01% (v/v)Nonidet-P40 (Sigma)] were added and the mixture was incubated for 15 minat 22° C. to allow pre-binding of the test compounds to the enzymebefore the start of the kinase reaction. Then the kinase reaction wasstarted by the addition of 3 μl of a solution of adenosine-tri-phosphate(ATP, 16.7 μM=>final conc. in the 5 μl assay volume is 10 μM) andsubstrate (1.25 μM=>final conc. in the 5 μl assay volume is 0.75 μM) inassay buffer and the resulting mixture was incubated for a reaction timeof 25 min at 22° C. The concentration of CDK2/CycE was adjusteddepending of the activity of the enzyme lot and was chosen appropriateto have the assay in the linear range, typical concentrations were inthe range of 130 ng/ml. The reaction was stopped by the addition of 5 μlof a solution of TR-FRET detection reagents (0.2 μM streptavidine-XL665[Cisbio Bioassays, Codolet, France] and 1 nManti-RB(pSer807/pSer811)-antibody from BD Pharmingen [#558389] and 1.2nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, productno. AD0077, as an alternative a Terbium-cryptate-labeled anti-mouse IgGantibody from Cisbio Bioassays can be used]) in an aqueous EDTA-solution(100 mM EDTA, 0.2% (w/v) bovine serum albumin in 100 mM HEPES pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the formationof complex between the phosphorylated biotinylated peptide and thedetection reagents. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theEu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm was measuredin a TR-FRET reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.07 nM (20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 11 nM,3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, the dilution series preparedseparately before the assay on the level of the 100fold concentratedsolutions in DMSO by serial dilutions, exact concentrations may varydepending pipettors used) in duplicate values for each concentration andIC50 values were calculated using Genedata Screener™ software.

2b. CDK2/CycE High ATP Kinase Assay

CDK2/CycE-inhibitory activity of compounds of the present invention at 2mM adenosine-tri-phosphate (ATP) was quantified employing the CDK2/CycETR-FRET (TR-FRET=Time Resolved Fluorescence Energy Transfer) assay asdescribed in the following paragraphs.

Recombinant fusion proteins of GST and human CDK2 and of GST and humanCycE, expressed in insect cells (Sf9) and purified byGlutathion-Sepharose affinity chromatography, were purchase fromProQinase GmbH (Freiburg, Germany). As substrate for the kinase reactionbiotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus in amidform) was used which can be purchased e.g. form the company JERINIpeptide technologies (Berlin, Germany).

For the assay 50 nl of a 100fold concentrated solution of the testcompound in DMSO was pipetted into either a black low volume 384wellmicrotiter plate or a black 1536well microtiter plate (both GreinerBio-One, Frickenhausen, Germany), 2 μl of a solution of CDK2/CycE inaqueous assay buffer [50 mM Tris/HCl pH 8.0, 10 mM MgCl2, 1.0 mMdithiothreitol, 0.1 mM sodium ortho-vanadate, 0.01% (v/v) Nonidet-P40(Sigma)] were added and the mixture was incubated for 15 min at 22° C.to allow pre-binding of the test compounds to the enzyme before thestart of the kinase reaction. Then the kinase reaction was started bythe addition of 3 μl of a solution ATP (3.33 mM=>final conc. in the 5 μlassay volume is 2 mM) and substrate (1.25 μM=>final conc. in the 5 μlassay volume is 0.75 μM) in assay buffer and the resulting mixture wasincubated for a reaction time of 25 min at 22° C. The concentration ofCDK2/CycE was adjusted depending of the activity of the enzyme lot andwas chosen appropriate to have the assay in the linear range, typicalconcentrations were about 10 ng/ml. The reaction was stopped by theaddition of 3 μl of a solution of TR-FRET detection reagents (0.333 μMstreptavidine-XL665 [Cisbio Bioassays, Codolet, France] and 1.67 nManti-RB(pSer807/pSer811)-antibody from BD Pharmingen [#558389] and 2 nMLANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, productno. AD0077, as an alternative a Terbium-cryptate-labeled anti-mouse IgGantibody from Cisbio Bioassays can be used]) in an aqueous EDTA-solution(167 mM EDTA, 0.2% (w/v) bovine serum albumin in 100 mM HEPES pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the formationof complex between the phosphorylated biotinylated peptide and thedetection reagents. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theEu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm was measuredin a TR-FRET reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.07 nM (20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 11 nM,3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, the dilution series preparedseparately before the assay on the level of the 100fold concentratedsolutions in DMSO by serial dilutions, exact concentrations may varydepending pipettors used) in duplicate values for each concentration andIC50 values were calculated using Genedata Screener™ software.

3. Proliferation Assay:

Cultivated tumour cells (HeLa, human cervical tumour cells, ATCC CCL-2;NCI-H460, human non-small cell lung carcinoma cells, ATCC HTB-177; DU145, hormone-independent human prostate carcinoma cells, ATCC HTB-81;HeLa-MaTu-ADR, multidrug-resistant human cervical carcinoma cells,EPO-GmbH Berlin; Caco-2, human colorectal carcinoma cells, ATCC HTB-37;B16F10, mouse melanoma cells, ATCC CRL-6475) were plated at a density of5,000 cells/well (DU145, HeLa-MaTu-ADR), 3,000 cells/well (NCI-H460,HeLa), 1,500 cells/well (Caco-2), or 1,000 cells/well (B16F10) in a96-well multititer plate in 200 μL of their respective growth mediumsupplemented 10% fetal calf serum. After 24 hours, the cells of oneplate (zero-point plate) were stained with crystal violet (see below),while the medium of the other plates was supplemented with the testsubstances in various concentrations (0 μM, as well as in the range of0.0001-10 μM; the final concentration of the solvent dimethyl sulfoxidewas adjusted to 0.1%) using a Hewlett-Packard HP D300 Digital Dispenser.The cells were incubated for 4 days in the presence of test substances.Cell proliferation was determined by staining the cells with crystalviolet: the cells were fixed by adding 20 μl/measuring point of an 11%glutaric aldehyde solution for 15 minutes at room temperature. Afterthree washing cycles of the fixed cells with water, the plates weredried at room temperature. The cells were stained by adding 100μl/measuring point of a 0.1% crystal violet solution (pH 3.0). Afterthree washing cycles of the stained cells with water, the plates weredried at room temperature. The dye was dissolved by adding 100μl/measuring point of a 10% acetic acid solution. The extinction wasdetermined by photometry at a wavelength of 595 n. The change of cellnumber, in percent, was calculated by normalization of the measuredvalues to the extinction values of the zero-point plate (=0%) and theextinction of the untreated (0 m) cells (=100%). The IC₅₀ values(inhibitory concentration at 50% of maximal effect) were determined bymeans of a 4 parameter fit.

A2780 human ovarian carcinoma cells (ECACC #93112519) and non-adherentMOLM-13 human acute myeloid leukemia cells (DSMZ ACC 554) were seeded ata density of 3,000 cell/well (A2780) or 5,000 cells/well (MOLM-13) in a96-well multititer plate in 150 μL of growth medium supplemented 10%fetal calf serum. After 24 hours, cell viability of one plate(zero-point plate) was determined with the Cell Titre-Glo LuminescentCell Viability Assay (Promega), while the medium of the other plates wassupplemented with the test substances in various concentrations (0 μM,as well as in the range of 0.0001-10 μM; the final concentration of thesolvent dimethyl sulfoxide was adjusted to 0.1%) using a Hewlett-PackardHP D300 Digital Dispenser. Cell viability was assessed after 72-hourexposure with the Cell Titre-Glo Luminescent Cell Viability Assay(Promega). IC₅₀ values (inhibitory concentration at 50% of maximaleffect) were determined by means of a 4 parameter fit on measurementdata which were normalized to vehicle (DMSO) treated cells (=100%) andmeasurement readings taken immediately before compound exposure (=0%).

4. Equilibrium Shake Flask Solubility Assay:

4a) High Throughput Determination of Aqueous Drug Solubility (100 mmolarin DMSO)

The high throughput screening method to determine aqueous drugsolubility is based on: Thomas Onofrey and Greg Kazan, Performance andcorrelation of a 96-well high throughput screening method to determineaqueous drug solubility,http://www.millipore.com/publications.nsf/a73664f9f981af8c852569b9005b4eee/e565516fb76e743585256da30052db77/$FILE/AN1731EN00.pdf

The assay was run in a 96-well plate format. Each well was filled withan individual compound.

All pipetting steps were performed using a robot platform.

100 μl of a 10 mmolar solution of drug in DMSO were concentrated byvacuum centrifugation and resolved in 10 μl DMSO. 990 μl phosphatebuffer pH 6.5 were added. The content of DMSO amounts to 1%. Themultititer plate was put on a shaker and mixed for 24 hrs at roomtemperature. 150 μl of the suspension were transferred to a filtrationplate. After filtration using a vacuum manifold the filtrate was diluted1:400 and 1:8000. A second microtiter plate with 20 μl of a 10 mMsolution of drug in DMSO served for calibration. Two concentrations(0.005 μM and 0.0025 μM) were prepared by dilution in DMSO/water 1:1 andused for calibration. Filtrate and calibration plates were quantified byHPLC-MS/MS.

Chemicals: Preparation of 0.1 m Phosphate Buffer pH 6.5:

61.86 g NaCl and 39.54 mg KH₂PO₄ were solved in water and filled up to11. The mixture was diluted 1:10 with water and the pH adjusted to 6.5by NaOH.

Materials: Millipore MultiScreen_(HTS)-HV Plate 0.45 μm

Chromatographic conditions were as follows:HPLC column: Ascentis Express C18 2.7 μm 4.6×30 mmInjection volume: 1 μlFlow: 1.5 ml/minMobile phase: acidic gradient

-   -   A: Water/0.05% HCOOH    -   B: Acetonitrile/0.05% HCOOH    -   0 min→95% A 5% B    -   0.75 min→5% A 95% B    -   2.75 min→5% A 95% B    -   2.76 min→95% A 5% B    -   3 min→95% A 5% B

The areas of sample- and calibration injections were determined by usingmass spectrometry software (AB SCIEX: Discovery Quant 2.1.3. and Analyst1.6.1). The calculation of the solubility value (in mg/l) was executedby an inhouse developed Excel macro.

4b) Thermodynamic Solubility in Water from Powder

The thermodynamic solubility of compounds in water was determined by anequilibrium shake flask method (see for example: E. H. Kerns, L. Di:Drug-like Properties: Concepts, Structure Design and Methods, 276-286,Burlington, Mass., Academic Press, 2008). A saturated solution of thedrug was prepared and the solution was mixed for 24 h to ensure thatequilibrium was reached. The solution was centrifuged to remove theinsoluble fraction and the concentration of the compound in solution wasdetermined using a standard calibration curve. To prepare the sample, 2mg solid compound was weighed in a 4 mL glass vial. 1 mL phosphatebuffer pH 6.5 was added. The suspension was stirred for 24 hrs at roomtemperature. The solution was centrifuged afterwards. To prepare thesample for the standard calibration, 2 mg solid sample was dissolved in30 mL acetonitrile. After sonification the solution was diluted withwater to 50 mL. Sample and standards were quantified by HPLC withUV-detection. For each sample two injection volumes (5 and 50 μl) intriplicates were made. Three injection volumes (5 μl, 10 μl and 20 μl)were made for the standard.

Chromatographic Conditions:

HPLC column: Xterra MS C18 2.5 μm 4.6×30 mmInjection volume: Sample: 3×5 μl and 3×50 μl

-   -   Standard: 5 μl, 10 μl, 20 μl        Flow: 1.5 mL/min        Mobile phase: acidic gradient:    -   A: Water/0.01% TFA    -   B: Acetonitrile/0.01% TFA    -   0 min→95% A 5% B    -   0-3 min→35% A 65% B, linear gradient    -   3-5 min→35% A 65% B, isocratic    -   5-6 min→95% A 5% B, isocratic        UV detector: wavelength near the absorption maximum (between 200        and 400 nm)

The areas of sample- and standard injections as well as the calculationof the solubility value (in mg/1) were determined by using HPLC software(Waters Empower 2 FR).

4c) Thermodynamic Solubility in Citrate Buffer pH 4

Thermodynamic solubility was determined by an equilibrium shake flaskmethod [Literature: Edward H. Kerns and Li Di (2008) Solubility Methodsin: Drug-like Properties: Concepts, Structure Design and Methods, p276-286. Burlington, Mass.: Academic Press].

A saturated solution of the drug was prepared and the solution was mixedfor 24 h to ensure that equilibrium has been reached. The solution wascentrifuged to remove the insoluble fraction and the concentration ofthe compound in solution was determined using a standard calibrationcurve.

To prepare the sample, 1.5 mg solid compound was weighed in a 4 ml glassvial. 1 ml Citrate buffer pH 4 was added. The suspension was put on astirrer and mixed for 24 hrs at room temperature. The solution wascentrifuged afterwards. To prepare the sample for the standardcalibration, 0.6 mg solid sample was dissolved in 19 mlacetonitrile/water 1:1. After sonification the solution was filled upwith acetonitrile/water 1:1 to 20 ml.

Sample and standards were quantified by HPLC with UV-detection. For eachsample two injection volumes (5 and 50 μl) in triplicates were made.Three injection volumes (5 μl, 10 μl and 20 μl) were made for thestandard.

Chemicals:

Citrate buffer pH 4 (MERCK Art. 109435; 1 L buffer consisting of 11,768g citric acid, 4,480 g sodium hydroxide, 1,604 g hydrogen chloride)Chromatographic conditions were as follows:HPLC column: Xterra MS C18 2.5 μm 4.6×30 mmInjection volume: Sample: 3×5 μl and 3×50 μl

-   -   Standard: 5 μl, 10 μl, 20 μl        Flow: 1.5 ml/min        Mobile phase: acidic gradient:    -   A: Water/0.01% TFA    -   B: Acetonitrile/0.01% TFA    -   0 min: 95% A 5% B    -   0-3 min: 35% A 65% B, linear gradient    -   3-5 min: 35% A 65% B, isocratic    -   5-6 min: 95% A 5% B, isocratic        UV detector: wavelength near the absorption maximum (between 200        and 400 nm)

The areas of sample- and standard injections as well as the calculationof the solubility value (in mg/1) were determined by using HPLC software(Waters Empower 2 FR).

The areas of sample- and standard injections as well as the calculationof the solubility value (in mg/1) were determined by using HPLC software(Waters Empower 2 FR).

5. Caco-2 Permeation Assay:

Caco-2 cells (purchased from DSMZ Braunschweig, Germany) were seeded ata density of 4.5×10⁴ cells per well on 24 well insert plates, 0.4 μmpore size, and grown for 15 days in DMEM medium supplemented with 10%fetal bovine serum, 1% GlutaMAX (100×, GIBCO), 100 U/mL penicillin, 100μg/mL streptomycin (GIBCO) and 1% non essential amino acids (100×).Cells were maintained at 37° C. in a humified 5% CO₂ atmosphere. Mediumwas changed every 2-3 day. Before running the permeation assay, theculture medium was replaced by a FCS-free hepes-carbonate transportbuffer (pH 7.2). For assessment of monolayer integrity thetransepithelial electrical resistance (TEER) was measured. Testcompounds were predissolved in DMSO and added either to the apical orbasolateral compartment in final concentration of 2 μM in transportbuffer. Before and after 2 h incubation at 37° C. samples were takenfrom both compartments. Analysis of compound content was done afterprecipitation with methanol by LC/MS/MS analysis. Permeability (Papp)was calculated in the apical to basolateral (A→B) and basolateral toapical (B→A) directions.

The apparent permeability was calculated using following equation:

Papp=(Vr/Po)(1/S)(P2/t)

Where Vr is the volume of medium in the receiver chamber, Po is themeasured peak area or height of the test drug in the donor chamber att=o, S the surface area of the monolayer, P2 is the measured peak areaof the test drug in the acceptor chamber after 2 h of incubation, and tis the incubation time. The efflux ratio basolateral (B) to apical (A)was calculated by dividing the Papp B-A by the Papp A-B. In addition thecompound recovery was calculated.

6. Investigation of In Vitro Metabolic Stability in Rat Hepatocytes

Hepatocytes from Han Wistar rats were isolated via a 2-step perfusionmethod. After perfusion, the liver was carefully removed from the rat:the liver capsule was opened and the hepatocytes were gently shaken outinto a Petri dish with ice-cold Williams medium E (purchased from SigmaAldrich Life Science, St Louis, Mo.). The resulting cell suspension wasfiltered through sterile gaze in 50 ml falcon tubes and centrifuged at50×g for 3 min at room temperature. The cell pellet was resuspended in30 ml WME and centrifuged through a Percoll® gradient for 2 times at100×g. The hepatocytes were washed again with Williams' medium E (WME)and resuspended in medium containing 5% Fetal calf serum (FCS, purchasedfrom Invitrogen, Auckland, NZ). Cell viability was determined by trypanblue exclusion.

For the metabolic stability assay liver cells were distributed in WMEcontaining 5% FCS to glass vials at a density of 1.0×10⁶ vital cells/ml.The test compound was added to a final concentration of 1 μM. Duringincubation, the hepatocyte suspensions were continuously shaken andaliquots were taken at 2, 8, 16, 30, 45 and 90 min, to which equalvolumes of cold acetonitrile were immediately added. Samples were frozenat −20° C. over night, after subsequently centrifuged for 15 minutes at3000 rpm and the supernatant was analyzed with an Agilent 1200HPLC-system with LCMS/MS detection.

The half-life of a test compound was determined from theconcentration-time plot. From the half-life the intrinsic clearanceswere calculated. Together with the additional parameters liver bloodflow, amount of liver cells in vivo and in vitro, the maximal oralbioavailability (Fmax) was calculated using the following scalingparameters: Liver blood flow (rat)—4.2 L/h/kg; specific liver weight—32g/kg rat body weight; liver cells in vivo- 1.1×10⁸ cells/g liver, livercells in vitro—0.5×10⁶/ml.

7. In Vivo Pharmacokinetics in Rats

For in vivo pharmacokinetic experiments test compounds were administeredto male Wistar rats intravenously at doses of 0.3 to 1 mg/kg formulatedas solutions using either rat plasma or solubilizers such as PEG400 inwell-tolerated amounts.

For pharmacokinetics after intravenous administration test compoundswere given as i.v. bolus and blood samples were taken at 2 min, 8 min,15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after dosing.Depending on the expected half-life additional samples were taken atlater time points (e.g. 48 h, 72 h). Blood was collected intoLithium-Heparin tubes (Monovetten®, Sarstedt) and centrifuged for 15 minat 3000 rpm. An aliquot of 100 μL from the supernatant (plasma) wastaken and precipitated by addition of 400 μL ice cold acetonitrile andfrozen at −20° C. over night. Samples were subsequently thawed andcentrifuged at 3000 rpm, 4° C. for 20 minutes. Aliquots of thesupernatants were taken for analytical testing using an Agilent 1200HPLC-system with LCMS/MS detection. PK parameters were calculated bynon-compartmental analysis using a PK calculation software.

PK parameters derived from concentration-time profiles after i.v.:CLplasma: Total plasma clearance of test compound (in L/kg/h); CLblood:Total blood clearance of test compound: CLplasma*Cp/Cb (in L/kg/h) withCp/Cb being the ratio of concentrations in plasma and blood, AUCnorm:Area under the concentration-time curve from t=0 h to infinity(extrapolated) divided by the administered dose (in kg*h/L); t_(1/2):terminal half-life (in h).

8. Surface Plasmon Resonance PTEFb

DEFINITIONS

The term “surface plasmon resonance”, as used herein, refers to anoptical phenomenon that allows for the analysis of the reversibleassociations of biological molecules in real time within a biosensormatrix, for example using the Biacore® system (GE HealthcareBiosciences, Uppsala, Sweden). Biacore® uses the optical properties ofsurface plasmon resonance (SPR) to detect alterations in the refractiveindex of a buffer, which changes as molecules in solution interact withthe target immobilized on the surface. In brief, proteins are covalentlybound to the dextran matrix at a known concentration and a ligand forthe protein is injected through the dextran matrix. Near infrared light,directed onto the opposite side of the sensor chip surface is reflectedand also induces an evanescent wave in the gold film, which in turn,causes an intensity dip in the reflected light at a particular angleknown as the resonance angle. If the refractive index of the sensor chipsurface is altered (e.g. by compound binding to the bound protein) ashift occurs in the resonance angle. This angle shift can be measured.These changes are displayed with respect to time along the y-axis of asensorgram, which depicts the association and dissociation of anybiological reaction.

The term “K_(D)”, as used herein, is intended to refer to theequilibrium dissociation constant of a particular compound/targetprotein complex.

The term “k_(off)”, as used herein, is intended to refer to theoff-rate, i.e. the dissociation rate constant of a particularcompound/target protein complex.

The term “target residence time”, as used herein, is intended to referto the inverse of the rate of dissociation rate constant (1/k_(off)) ofa particular compound/target protein complex.

For further descriptions see:

JMnsson U et al al., 1993 Ann Biol Clin.; 51(1):19-26. Johnsson B et al,Anal Biochem. 1991; 198(2):268-77. Day Y et al, Protein Science, 2002;11, 1017-1025 Myskza D G, Anal Biochem., 2004; 329, 316-323 Tummino andCopeland, Biochemistry, 2008; 47(20):5481-5492. Biological Activity

The biological activity (e.g. as inhibitors of PTEFb) of the compoundsaccording to the invention can be measured using the SPR assaydescribed.

The level of activity exhibited by a given compound in the SPR assay canbe defined in terms of the K_(D) value, and preferred compounds of thepresent invention are compounds having a K_(D) value of less than 1micromolar, more preferably less than 0.1 micromolar. Furthermore, thetime in residence at its target of a given compound can be defined interms of the target residence time (TRT), and preferred compounds of thepresent invention are compounds having a TRT value of more than 10minutes, more preferably more than 1 hour.

The ability of the compounds according to the invention to bind humanPTEFb may be determined using surface plasmon resonance (SPR). K_(D)values and k_(off) values may be measured using a Biacore® T200instrument (GE Healthcare, Uppsala, Sweden).

For SPR measurements, recombinant human PTEFb (CDK9/Cyclin T1recombinant human active protein kinase purchased from ProQinase,Freiburg, Germany) is immobilized using standard amine coupling(Johnsson B et al, Anal Biochem. 1991 Nov. 1; 198(2):268-77). Briefly,carboxymethylated dextran biosensor chips (CM7, GE Healthcare) areactivated with N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimidehydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to thesupplier's instructions. Human PTEFb is diluted in 1×HBS-EP+ (GEHealthcare) and injected on the activated chip surface. Subsequently, a1:1 solution of 1 M ethanolamine-HCl (GE Healthcare) and 1×HBS-EP isinjected to block unreacted groups, resulting in approximately 4000response units (RU) of immobilized protein. A reference surface isgenerated by treatment with NHS-EDC and ethanolamine-HCl. Compounds aredissolved in 100% dimethylsulfoxide (DMSO, Sigma-Aldrich, Germany) to aconcentration of 10 mM and subsequently diluted in running buffer(1×HBS-EP+ pH 7.4 [generated from HBS-EP+ Buffer 10× (GE Healthcare):0.1 M HEPES, 1.5 M NaCl, 30 mM EDTA and 0.5% v/v Surfactant P20], 1% v/vDMSO). For kinetic measurements, serial dilutions of compound (0.78 nMup to 25 nM) are injected over immobilized protein. Binding kinetics ismeasured at 37° C. with a flow rate of 100 μl/min in running buffer.Compound concentrations are injected for 70 s followed by a dissociationtime of 1100 s. The resulting sensorgrams are double-referenced againstthe reference surface as well as against blank injections.

The double-referenced sensorgrams are fit to a simple reversibleLangmuir 1:1 reaction mechanism as implemented in the Biacore® T200evaluation software 2.0 (GE Healthcare). In cases were full compounddissociation has not occurred at the end of the dissociation phase, theRmax parameter (response at saturation) is fit as local variable. In allother cases, Rmax is fit as global variable. SPR measurements aresummarized in Table 4

Syntheses of Compounds

The syntheses of the macrocyclic compounds of formula (I) according tothe present invention are preferably carried out according to thegeneral synthetic sequences as shown in Schemes 1a, 1b, 1c, 2a and 2b.

In addition to said routes described below, also other routes may beused to synthesise the target compounds, in accordance with commongeneral knowledge of a person skilled in the art of organic synthesis.The order of transformations exemplified in the following Schemes istherefore not intended to be limiting, and suitable synthesis steps fromvarious schemes can be combined to form additional synthesis sequences.In addition, modification of any of the substituents R¹, R², R³, R⁴, R⁵and/or Z can be achieved before and/or after the exemplifiedtransformations. These modifications can be such as the introduction ofprotective groups, cleavage of protective groups, reduction or oxidationof functional groups, halogenation, metallation, metal catalysedcoupling reactions, substitution or other reactions known to a personskilled in the art. These transformations include those which introducea functionality allowing for further interconversion of substituents.Appropriate protective groups and their introduction and cleavage arewell-known to a person skilled in the art (see for example T. W. Greeneand P. G. M. Wuts in Protective Groups in Organic Synthesis, 4^(th)edition, Wiley 2006). Specific examples are described in the subsequentparagraphs. Further, it is possible that two or more successive stepsmay be performed without work-up being performed between said steps,e.g. a “one-pot” reaction, as it is well-known to a person skilled inthe art.

The geometry of the sulfoximine, sulfodiimine and sulfoxide moietyrenders some of the compounds of the general formula (I) chiral.Separation of racemic sulfoximines, sulfodiimines and sulfoxides intotheir enantiomers can be achieved by methods known to the person skilledin the art, preferably by means of preparative HPLC on chiral stationaryphase.

The syntheses of the pyridine derivatives of formulae (Ia), (Ib) and(Ic), all of them constituting subsets of the general formula (I)according to the present invention, are preferably carried out accordingto the general synthetic sequences as shown in Schemes 1a, 1b and 1c and1d.

Schemes 1a, 1b and 1c, wherein R¹, R², R³, R⁴, R⁵, Z and L are asdefined for the compound of general formula (I) according to the presentinvention, outline the preparation of pyridine-based macrocycliccompounds of formulae (Ia), (Ib) and (Ic), from2-chloro-5-fluoro-4-iodopyridine (1; CAS #884494-49-9).

Said starting material (1) can be reacted with a boronic acid derivativeof formula (2), in which R³, R⁴ and Z are as defined for the compound ofgeneral formula (I), to give a compound of formula (3). The boronic acidderivative (2) may be a boronic acid (R=—H) or an ester of the boronicacid, e.g. its isopropyl ester (R=—CH(CH₃)₂), preferably an esterderived from pinacol in which the boronic acid intermediate forms a2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (R—R=—C(CH₃)₂—C(CH₃)₂—).

Said coupling reaction can be catalyzed by palladium catalysts, e.g. byPd(0) catalysts such as tetrakis(triphenylphosphine)palladium(0)[Pd(PPh₃)₄], tris(dibenzylideneacetone)di-palladium(0) [Pd₂(dba)₃], orby Pd(II) catalysts such asdichlorobis(triphenylphosphine)-palladium(II) [Pd(PPh₃)₂Cl₂],palladium(II) acetate and triphenylphosphine or by[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride.

The reaction can preferably be carried out in a mixture of a solventsuch as 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol withwater and in the presence of a base such as potassium carbonate, sodiumbicarbonate or potassium phosphate.

(review: D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co.KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein).

The reaction can be performed at temperatures ranging from roomtemperature (i.e. approx. 20° C.) to the boiling point of the respectivesolvent. Further on, the reaction can be performed at temperatures abovethe boiling point using pressure tubes and a microwave oven. Thereaction is preferably completed after 1 to 36 hours of reaction time.

In the second step, a compound of formula (3) can be converted to acompound of formula (4). This reaction can be carried out by aPalladium-catalyzed C—N cross-coupling reaction (for a review on C—Ncross coupling reactions see for example: a) L. Jiang, S. L. Buchwald in‘Metal-Catalyzed Cross-Coupling Reactions’, 2^(nd) ed.: A. de Meijere,F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004).

Preferred is the herein described use of lithiumbis(trimethylsilyl)amide, tris(dibenzylideneacetone)dipalladium(0) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl in THF. Thereactions are preferably run under an atmosphere of argon for 3-24 hoursat 60° C. in an oil bath.

In the third step, a compound of formula (4) can be converted to acompound of formula (5), by means of cleaving the methyl ether presentin compounds of formula (4).

Preferred is the herein described use of boron tribromide in DCM. Thereactions are preferably run for 1-24 hours at 0° C. to roomtemperature.

In the fourth step, a compound of formula (5) can be coupled with acompound of formula (6), in which R¹, R² and L are as defined for thecompound of general formula (I) and in which LG represents a leavinggroup such as a chlorine atom, a bromine atom or a iodine atom,C₁-C₄-alkyl-S(═O)₂O—, trifluoromethanesulfonyloxy-, benzenesulfonyloxy-,or para-toluenesulfonyloxy-, to give a compound of formula (7).Preferred is the herein described use of potassium carbonate andpotassium iodide in DMF. The reactions are preferably run for 1-36 hoursat 40 to 80° C.

Compounds of the formula (6) can be prepared as outlined in Scheme Ic,infra.

In the fifth step, a compound of formula (7) is converted to amacrocycle of formula (Ia). This cyclization reaction can be carried outby a Palladium-catalyzed C—N cross-coupling reaction (for a review onC—N cross coupling reactions see for example: a) L. Jiang, S. L.Buchwald in ‘Metal-Catalyzed Cross-Coupling Reactions’, 2^(nd) ed.: A.de Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004).

Preferred is the herein described use ofchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct,2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl as catalyst andligand, an alkali carbonate or an alkali phosphate, preferably potassiumphosphate, as a base, in a mixture of a C₁-C₃-alkylbenzene and acarboxamide based solvent, preferably a mixture of toluene and NMP, as asolvent. The reactions are preferably run under an atmosphere of argonfor 2-24 hours at 100-130° C. in a microwave oven or in an oil bath.

In the sixth step, the tert-butoxycarbonyl-group attached to thesulfoximine nitrogen can be cleaved under acidic conditions to give anunprotected sulfoximine of formula (Ib) (see for example: J. A. Bull, J.Org. Chem. 2015, 80, 6391).

Preferred is the herein described use of an acid, preferablytrifluoroacetic acid in dichloromethane as a solvent.

Said N-unprotected sulfoximine of formula (Ib) (R⁵═H) may be furtherconverted into a N-functionalized derivative of formula (Ic). There aremultiple methods for the preparation of N-functionalized sulfoximines byfunctionalization of the nitrogen of the sulfoximine group:

-   -   Alkylation: see for example: a) U. Lücking et al, US        2007/0232632; b) C. R. Johnson, J. Org. Chem. 1993, 58,        1922; c) C. Bolm et al, Synthesis 2009, 10, 1601.    -   Acylation: see for example: a) C. Bolm et al, Chem. Europ. J.        2004, 10, 2942; b) C. Bolm et al, Synthesis 2002, 7, 879; c) C.        Bolm et al, Chem. Europ. J. 2001, 7, 1118.    -   Arylation: see for example: a) C. Bolm et al, Tet. Lett. 1998,        39, 5731; b) C. Bolm et al., J. Org. Chem. 2000, 65, 169; c) C.        Bolm et al, Synthesis 2000, 7, 911; d) C. Bolm et al, J. Org.        Chem. 2005, 70, 2346; e) U. Lücking et al, WO2007/71455.    -   Reaction with isocyanates: see for example: a) V. J. Bauer et        al, J. Org. Chem. 1966, 31, 3440; b) C. R. Johnson et al, J. Am.        Chem. Soc. 1970, 92, 6594; c) S. Allenmark et al, Acta Chem.        Scand. Ser. B 1983, 325; d) U. Lücking et al, US2007/0191393.    -   Reaction with sulfonylchlorides: see for example: a) D. J. Cram        et al, J. Am. Chem. Soc. 1970, 92, 7369; b) C. R. Johnson et        al, J. Org. Chem. 1978, 43, 4136; c) A. C. Barnes, J. Med. Chem.        1979, 22, 418; d) D. Craig et al, Tet. 1995, 51, 6071; e) U.        Lücking et al, US2007/191393.    -   Reaction with chloroformiates: see for example: a) P. B. Kirby        et al, DE2129678; b) D. J. Cram et al, J. Am. Chem. Soc. 1974,        96, 2183; c) P. Stoss et al, Chem. Ber. 1978, 111, 1453; d) U.        Lücking et al, WO2005/37800.    -   Reaction with bromocyane: see for example: a) D. T. Sauer et al,        Inorganic Chemistry 1972, 11, 238; b) C. Bolm et al, Org. Lett.        2007, 9, 2951; c) U. Lücking et al, WO 2011/29537.

Intermediates of the formula (6), in which R¹, R² and L are as definedfor the compound of general formula (I) according to the presentinvention and in which LG represents a leaving group such as a chlorineatom, a bromine atom or a iodine atom, C₁-C₄-alkyl-S(═O)₂O—,trifluoromethanesulfonyloxy-, benzenesulfonyloxy-, orpara-toluenesulfonyloxy-, can be prepared according to Scheme 1c,starting e.g. from a 2,6-dichloroisonicotinic acid derivative of formula(8), in which R² is as defined for the compound of general formula (I),which can be reduced to the corresponding pyridinemethanol of formula(9), by means of reduction. Preferred is the herein described use ofsulfanediyldimethane-borane (1:1 complex) in tetrahydrofuran.

Derivatives of isonicotinic acid of formula (8), and esters thereof, arewell known to the person skilled in the art, and are often commerciallyavailable.

In a second step, said pyridinemethanol of formula (9) can be reacted togive a compound of formula (10), in which LG represents a leaving groupsuch as a chlorine atom, a bromine atom or a iodine atom,C₁-C₄-alkyl-S(═O)₂O—, trifluoromethanesulfonyloxy-, benzenesulfonyloxy-,or para-toluenesulfonyloxy-. Such conversions are well known to theperson skilled in the art; preferred is the herein described use ofmethanesulfonyl chloride in the presence of triethylamine as a base, indichloromethane as a solvent, to give a compound of formula (10) inwhich LG represents methanesulfonyloxy-.

In a third step, a compound of formula (10) can be reacted with a thiolof the formula R¹—SH, in which R¹ is as defined for the compound ofgeneral formula (I), to give a thioether derivative of formula (11).Thiols of the formula R¹SH are well known to the person skilled in theart and are commercially available in considerable variety.

In a fourth step, a thioether derivative of formula (11) can be reactedwith an anion formed in situ from a diol of the formula HO-L-OH, inwhich L is as defined for the compound of general formula (I), and analkali metal, preferably sodium, or sodium hydride in tetrahydrofuran asa solvent, to give intermediate compounds of formula (12).

In a fifth step, oxidation of a thioether of formula (12) can be used toobtain the corresponding sulfoxide of formula (13). The oxidation can beperformed analogously to known processes (see for example: (a) M. H. Aliet al, Synthesis 1997, 764; (b) M. C. Carreno, Chem. Rev. 1995, 95,1717; (c) I. Patel et al, Org. Proc. Res. Dev. 2002, 6, 225; (d) N.Khiar et al, Chem. Rev. 2003, 103, 3651).

Preferred is the herein described use of periodic acid und iron(III)chloride.

In a sixth step, Rhodium-catalyzed imination of a sulfoxide of formula(13) can be used to prepare the N-Boc-protected sulfoximines of formula(14) (Bull et al, J. Org. Chem. 2015, 80, 6391). Preferred is the hereindescribed use of sulfoxide (13), tert-butyl carbamate, magnesium oxide,rhodium(II) acetate dimer and iodobenzene diacetate in DCM at roomtemperature to 45° C.

In a seventh step, the alcohol can be reacted with methanesulfonylchloride to form the methanesulfonate (6).

Preferred is the herein described use of trimethylamine as the base inDCM as the solvent at room temperature.

In alternative approach is outlined in Scheme Id.

In the first step, a compound of formula (5) can be coupled with analcohol LG-L-OH, in which L is as defined for the compound of generalformula (I) and in which LG represents a leaving group such as achlorine atom, a bromine atom or a iodine atom, C₁-C₄-alkyl-S(═O)₂O—,trifluoromethanesulfonyloxy-, benzenesulfonyloxy-, orpara-toluenesulfonyloxy-, to give a compound of formula (28). Preferredis the herein described use a CH₃—S(═O)₂O— leaving group in combinationwith potassium carbonate and potassium iodide in DMF. The reactions arepreferably run for 1-36 hours at 40 to 80° C.

In the second step, a compound of formula (28) can be coupled with acompound of formula (29) to give a compound of formula (30).

This reaction can be carried out by a Mitsunobu reaction (see forexample: a) K. C. K. Swamy et al, Chem. Rev. 2009, 109, 2551).

In the third step, a compound of formula (30) can be converted to amacrocycle compound of the invention (Ig), which constitutes a subset ofthe general formula (I) according to the present invention, Thiscyclization reaction can be carried out by a Palladium-catalyzed C—Ncross-coupling reaction (for a review on C—N cross coupling reactionssee for example: a) L. Jiang, S. L. Buchwald in ‘Metal-CatalyzedCross-Coupling Reactions’, 2^(nd) ed.: A. de Meijere, F. Diederich,Eds.: Wiley-VCH: Weinheim, Germany, 2004).

Preferred is the herein described use ofchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct,2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl as catalyst andligand, an alkali carbonate or an alkali phosphate, preferably potassiumphosphate, as a base, in a mixture of a C₁-C₃-alkylbenzene and acarboxamide based solvent, preferably a mixture of toluene and NMP, as asolvent. The reactions are preferably run under an atmosphere of argonfor 2-24 hours at 100-130° C. in a microwave oven or in an oil bath.

In the last step, oxidation of a thioether of formula (Ig) can be usedto obtain the corresponding sulfone of formula (Ih), which constitutes asubset of the general formula (I) according to the present invention.The oxidation can be performed analogously to known processes.

Preferred is the herein described use of 3-chloroperbenzoic acid in DCM.

Alternatively, In the last step, one-pot oxidation/imination reaction ofa thioether of formula (Ig) can be used to obtain the corresponding NHsulfoximine of formula (Ib), which constitutes a subset of the generalformula (I) according to the present invention.

Preferred is the herein described procedure based on A. Tota, M.Zenzola, S. J. Chawner, S. St. John-Campell, C. Carlucci, G. Romanazzi,L. Degennaro, J. A. Bull, R. Luisi; ChemComm 2017, 348

The syntheses of the pyrimidine derivatives of formulae (Id), (Ie) and(If), all of them also constituting subsets of the general formula (I)according to the present invention, are preferably carried out accordingto the general synthetic sequences as shown in Schemes 2a and 2b.

Schemes 2a and 2b, wherein R¹, R², R³, R⁴, R⁵, Z and L are as definedfor the compound of general formula (I) according to the presentinvention, outline the preparation of pyrimidine compounds of thegeneral formula (Id), (Ie) and (If) from 2,4-dichloro-5-fluoropyrimidine(CAS #2927-71-1), (15). Said starting material (15) can be reacted witha boronic acid derivative of formula (2) to give a compound of formula(16). The boronic acid derivative (2) may be a boronic acid (R=—H) or anester of the boronic acid, e.g. its isopropyl ester (R=—CH(CH₃)₂),preferably an ester derived from pinacol in which the boronic acidintermediate forms a 2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(R—R=—C(CH₃)₂—C(CH₃)₂—). Boronic acids and their esters are commerciallyavailable and well-known to the person skilled in the art; see e.g. D.G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim,ISBN 3-527-30991-8 and references cited therein.

The coupling reaction is catalyzed by Pd catalysts, e.g. by Pd(0)catalysts such as tetrakis(triphenylphosphine)palladium(0) [Pd(PPh₃)₄],tris(dibenzylideneacetone)di-palladium(0) [Pd₂(dba)₃], or by Pd(II)catalysts such as dichlorobis(triphenylphosphine)-palladium(II)[Pd(PPh₃)₂Cl₂], palladium(II) acetate and triphenylphosphine or by[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride[Pd(dppf)Cl₂].

The reaction can preferably be carried out in a mixture of a solventsuch as 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol withwater and in the presence of a base such as aqueous potassium carbonate,aqueous sodium bicarbonate or potassium phosphate.

The reaction can be performed at temperatures ranging from roomtemperature (=20° C.) to the boiling point of the solvent. Further on,the reaction can be performed at temperatures above the boiling pointusing pressure tubes and a microwave oven. (review: D. G. Hall, BoronicAcids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN3-527-30991-8 and references cited therein).

The reaction is preferably completed after 1 to 36 hours of reactiontime.

In the second step, a compound of formula (16) can be coupled with acompound of formula (17) to give a compound of formula (18).

This reaction can be carried out by a Mitsunobu reaction (see forexample: a) K. C. K. Swamy et al, Chem. Rev. 2009, 109, 2551).

Compounds of the formula (17) can be prepared as outlined in Scheme 2b,infra.

Said compounds of formula (18) (Scheme 2a), wherein R¹, R², R³, R⁴, Land Z are defined for the compound of general formula (I) according tothe present invention, can be reduced to give an aniline of formula(19). The reduction can be prepared analogously to known processes (seefor example: (a) Sammond et al; Bioorg. Med. Chem. Lett. 2005, 15, 3519;(b) R. C. Larock, Comprehensive Organic Transformations, VCH, New York,1989, 411-415). Preferred is the herein described use of Platinum 1% andvanadium 2%, on activated carbon in methanol and THF at room temperatureunder a hydrogen atmosphere.

In the fourth step, a compound of formula (19) can be converted to amacrocycle compound of the invention (Id). This cyclization reaction canbe carried out by a Palladium-catalyzed C—N cross-coupling reaction (fora review on C—N cross coupling reactions see for example: a) L. Jiang,S. L. Buchwald in ‘Metal-Catalyzed Cross-Coupling Reactions’, 2^(nd) aed.: A. de Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany,2004).

Preferred is the herein described use ofchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct,2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl as catalyst andligand, an alkali carbonate or an alkali phosphate, preferably potassiumphosphate, as a base, in a mixture of a C₁-C₃-alkylbenzene and acarboxamide based solvent, preferably a mixture of toluene and NMP, as asolvent. The reactions are preferably run under an atmosphere of argonfor 2-24 hours at 100-130° C. in a microwave oven or in an oil bath.

In the fifth step, the tert-butoxycarbonyl-group attached to thesulfoximine nitrogen can be cleaved under acidic conditions to give anunprotected sulfoximine of formula (Ie) (see for example: J. A. Bull, J.Org. Chem. 2015, 80, 6391).

Preferred is the herein described use of an acid, preferablytrifluoroacetic acid in dichloromethane as a solvent.

Said N-unprotected sulfoximine of formula (Ie) (R⁵=H) may be furtherconverted into a N-functionalized derivative of formula (If). There aremultiple methods for the preparation of N-functionalized sulfoximines byfunctionalization of the nitrogen of the sulfoximine group:

-   -   Alkylation: see for example: a) U. Lücking et al, US        2007/0232632; b) C. R. Johnson, J. Org. Chem. 1993, 58,        1922; c) C. Bolm et al, Synthesis 2009, 10, 1601.    -   Acylation: see for example: a) C. Bolm et al, Chem. Europ. J.        2004, 10, 2942; b) C. Bolm et al, Synthesis 2002, 7, 879; c) C.        Bolm et al, Chem. Europ. J. 2001, 7, 1118.    -   Arylation: see for example: a) C. Bolm et al, Tet. Lett. 1998,        39, 5731; b) C. Bolm et al., J. Org. Chem. 2000, 65, 169; c) C.        Bolm et al, Synthesis 2000, 7, 911; d) C. Bolm et al, J. Org.        Chem. 2005, 70, 2346; e) U. Lücking et al, WO2007/71455.    -   Reaction with isocyanates: see for example: a) V. J. Bauer et        al, J. Org. Chem. 1966, 31, 3440; b) C. R. Johnson et al, J. Am.        Chem. Soc. 1970, 92, 6594; c) S. Allenmark et al, Acta Chem.        Scand. Ser. B 1983, 325; d) U. Lücking et al, US2007/0191393.    -   Reaction with sulfonylchlorides: see for example: a) D. J. Cram        et al, J. Am. Chem. Soc. 1970, 92, 7369; b) C. R. Johnson et        al, J. Org. Chem. 1978, 43, 4136; c) A. C. Barnes, J. Med. Chem.        1979, 22, 418; d) D. Craig et al, Tet. 1995, 51, 6071; e) U.        Lücking et al, US2007/191393.    -   Reaction with chloroformiates: see for example: a) P. B. Kirby        et al, DE2129678; b) D. J. Cram et al, J. Am. Chem. Soc. 1974,        96, 2183; c) P. Stoss et al, Chem. Ber. 1978, 111, 1453; d) U.        Lücking et al, WO2005/37800.    -   Reaction with bromocyane: see for example: a) D. T. Sauer et al,        Inorganic Chemistry 1972, 11, 238; b) C. Bolm et al, Org. Lett.        2007, 9, 2951; c) U. Lücking et al, WO 2011/29537.

Compounds of the formula (17), in which R¹, R² and L are as defined forthe compound of general formula (I) according to the present invention,can be prepared according to Scheme 2b, starting e.g. from a benzylicalcohol derivative of formula (20), in which R² is as defined for thecompound of general formula (I), is reacted to give a compound offormula (21), in which LG represents a leaving group such as a chlorineatom, a bromine atom or an iodine atom, C₁-C₄-alkyl-S(═O)₂O—,trifluoromethanesulfonyloxy-, benzenesulfonyloxy-, orpara-toluenesulfonyloxy-. Such conversions are well known to the personskilled in the art; preferred is the herein described use of thionylchloride in N,N-dimethylformamide (DMF) as a solvent, to give a compoundof formula (21) in which LG represents a chlorine atom.

Benzylic alcohol derivative of formula (20), or the correspondingcarboxylic acids and their esters, are known to the person skilled inthe art, and are commercially available in certain cases.

In a second step, a compound of formula (21) can be reacted with a thiolof the formula R¹—SH, in which R¹ is as defined for the compound ofgeneral formula (I), to give a thioether derivative of formula (22).

Thiols of the formula R¹SH are well known to the person skilled in theart and are commercially available in considerable variety.

In a third step, a thioether derivative of formula (22) can be reactedwith a carboxylic ester of formula (23), in which L′ represents aC₂-C₇-alkylene group featuring one carbon atom less as compared to thecorresponding group L in formula (17), R^(E) represents a C₁-C₄-alkylgroup, and in which LG represents a leaving group such as a chlorineatom, a bromine atom or an iodine atom, CH₃—S(═O)₂O—,trifluoromethanesulfonyloxy-, benzenesulfonyloxy-, orpara-toluenesulfonyloxy-, in the presence of a base, such as an alkalicarbonate, preferably potassium carbonate, in N,N-dimethylformamide(DMF) as a solvent, to give a compound of formula (24).

In a fourth step, oxidation of a thioether of formula (24) can be usedto obtain the corresponding sulfoxide of formula (25) The oxidation canbe performed analogously to known processes (see for example: (a) M. H.Ali et al, Synthesis 1997, 764; (b) M. C. Carreno, Chem. Rev. 1995, 95,1717; (c) I. Patel et al, Org. Proc. Res. Dev. 2002, 6, 225; (d) N.Khiar et al, Chem. Rev. 2003, 103, 3651). Preferred is the hereindescribed use of periodic acid und iron(III) chloride.

In a fifth step, a Rhodium-catalyzed imination of a sulfoxide of formula(25) can be used to prepare the N-Boc-protected sulfoximines of formula(26) (Bull et al, J. Org. Chem. 2015, 80, 6391). Preferred is the hereindescribed use of sulfoxide, tert-butyl carbamate, magnesium oxide,rhodium(II) acetate dimer and iodobenzene diacetate in DCM at roomtemperature to 45° C.

In a sixth step, an ester of the formula (26) can be reduced using areducing agent such as lithium aluminium hydride ordi-iso-butylaluminiumhydride (DIBAL), in an ether, preferablytetrahydrofuran, as a solvent, to give compound of the formula (17)which can be further processed as shown in the Scheme 2a.

Abbreviations Used in the Description of the Chemistry and in theExamples that Follow are:

br. (broad, ¹H NMR signal); CDCl₃ (deuterated chloroform); cHex(cyclohexane); DCE (dichloroethane); d (doublet, ¹H NMR signal); DCM(dichloromethane); DIPEA (di-iso-propylethylamine); DMAP(4-N,N-dimethylaminopyridine), DME (1,2-dimethoxyethane), DMF(N,N-dimethylformamide); DMSO (dimethyl sulfoxide); ES (electrospray);EtOAc (ethyl acetate); EtOH (ethanol); h (hour(s)); ¹H NMR (protonnuclear magnetic resonance spectroscopy); HPLC (High Performance LiquidChromatography), iPrOH (iso-propanol); m (multiplet, ¹H NMR signal);mCPBA (meta-chloroperoxybenzoic acid), MeCN (acetonitrile), MeOH(methanol); min (minute(s)); MS (mass spectrometry); MTBE (methyltert-butyl ether); NMP (N-Methylpyrrolidin-2-one); NMR (nuclear magneticresonance); Pd(dppf)Cl₂ ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane); q (quartet, ¹H NMR signal);quin (quintet, ¹H NMR signal); rac (racemic); RT (room temperature); s(singlet, ¹H NMR signal); sat. aq. (saturated aqueous); SiO₂ (silicagel); t (triplet, ¹H NMR signal); TFA (trifluoroacetic acid); TFAA(trifluoroacetic anhydride), THF (tetrahydrofuran); UPLC (Ultra-HighPerformance Liquid Chromatography), UV (ultraviolet), wt-% (percent byweight).

¹H-NMR Spectra

¹H-NMR signals are specified with their multiplicity/combinedmultiplicities as apparent from the spectrum; possible higher-ordereffects are not considered. Chemical shifts of the signals (δ) arespecified as ppm (parts per million).

Chemical Naming:

Chemical names were generated using the ACD/Name software from ACD/Labs.In some cases generally accepted names of commercially availablereagents were used in place of ACD/Name generated names.

Salt Stoichiometry:

In the present text, in particular in the Experimental Section, for thesynthesis of intermediates and of examples of the present invention,when a compound is mentioned as a salt form with the corresponding baseor acid, the exact stoichiometric composition of said salt form, asobtained by the respective preparation and/or purification process, is,in most cases, unknown.

Unless specified otherwise, suffixes to chemical names or structuralformulae such as “hydrochloride”, “trifluoroacetate”, “sodium salt”, or“x HCl”, “x CF₃COOH”, “x Na*”, for example, are to be understood as nota stoichiometric specification, but solely as a salt form.

This applies analogously to cases in which synthesis intermediates orexample compounds or salts thereof have been obtained, by thepreparation and/or purification processes described, as solvates, suchas hydrates with (if defined) unknown stoichiometric composition.

Preparative HPLC Methods: Autopurifier: Acidic Conditions

System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767,CFO, DAD 2996, ELSD 2424, SQD Column: XBrigde C18 5 μm 100 × 30 mmSolvent: A = H₂O + 0.1 vol-% HCOOH (99%) B = MeCN Gradient: 0.00-0.50min 5% B, 25 mL/min 0.51-5.50 min 10-100% B, 70 mL/min 5.51-6.50 min100% B, 70 mL/min Temperature: RT Solution: max. 250 mg/max. 2.5 mL DMSOor DMF Injection: 1 × 2.5 ml Detection: DAD scan range 210-400 nm MSESI+, ESI−, scan range 160-1000 m/z

Autopurifier: Basic Conditions

System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767,CFO, DAD 2996, ELSD 2424, SQD Column: XBrigde C18 5 μm 100 × 30 mmSolvent: A = H₂O + 0.2% vol-% aqueous NH₃ (32%) B = MeCN Gradient:0.00-0.50 min 5% B, 25 mL/min 0.51-5.50 min 10-100% B, 70 mL/min5.51-6.50 min 100% B, 70 mL/min Temperature: RT Solution: max. 250mg/max. 2.5 mL DMSO or DMF Injection: 1 × 2.5 ml Detection: DAD scanrange 210-400 nm MS ESI+, ESI−, scan range 160-1000 m/z

General Methods for LC-MS Analysis Method a:

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEHC18 1.7 μm, 50×2.1 mm; eluent A: water+0.1 vol % formic acid (99%),eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B;flow 0.8 ml/min; temperature: 60° C.; DAD scan: 210-400 nm.

Method b:

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEHC18 1.7 μm, 50×2.1 mm; eluent A: water+0.2 vol % aqueous ammonia (32%),eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B;flow 0.8 ml/min; temperature: 60° C.; DAD scan: 210-400 n.

Example 1 (rac)-tert-butyl[{[3,20-difluoro-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate

Preparation of Intermediate 1.1:2-chloro-5-fluoro-4-(4-fluoro-3-methoxyphenyl)pyridine

A batch with 2-chloro-5-fluoro-4-iodopyridine [CAS-RN: 884494-49-9](3000 mg; 11.65 mmol), (4-fluoro-3-methoxyphenyl)boronic acid [CAS-RN:854778-31-7] (1981 mg; 11.65 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [CAS-RN:72287-26-4] (952 mg; 1.17 mmol) in 1,2-dimethoxyethane (30.0 mL) and 2 Maqueous solution of potassium carbonate (23 mL) was degassed usingargon. The batch was stirred under an atmosphere of argon for 4 hours at100° C. After cooling, the batch was diluted with ethyl acetate and THFand washed with a saturated aqueous solution of sodium chloride. Theorganic layer was filtered using a Whatman filter and concentrated. Theresidue was purified by column chromatography (hexane to hexane/ethylacetate 50%) to give the title compound (2600 mg; 10.2 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=3.92 (s, 3H), 7.28 (ddt, 1H), 7.39(dd, 1H), 7.48 (dd, 1H), 7.86 (d, 1H), 8.55 (d, 1H).

Preparation of Intermediate 1.2:5-fluoro-4-(4-fluoro-3-methoxyphenyl)pyridin-2-amine

A solution of lithium bis(trimethylsilyl)amide in THF (1M; 10.2 mL;10.17 mmol; Aldrich Chemical Company Inc.) [CAS-RN: 4039-32-1] was addedto a mixture of 2-chloro-5-fluoro-4-(4-fluoro-3-methoxyphenyl)pyridine(1.30 g; 5.09 mmol; see Intermediate 1.1),tris(dibenzylideneacetone)dipalladium (0) (0.09 g; 0.10 mmol; AldrichChemical Company Inc.) [CAS-RN: 51364-51-3] and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.10 g; 0.20mmol; Aldrich Chemical Company Inc.) [CAS-RN: 564483-18-7] in THF (10.4mL) under an atmosphere of argon at room temperature. The mixture wasstirred at 60° C. for 5 hours. The mixture was cooled to −20° C. and thepH was adjusted under cooling to 4-6 by the addition of aqueous hydrogenchloride solution (1N). The mixture was stirred at room temperature for15 minutes before the pH was adjusted to 11 by the addition of aqueoussodium hydroxide solution (2N). The mixture was three times extractedwith ethyl acetate. The combined organic layers were filtered using aWhatman filter and concentrated. The residue was purified by columnchromatography on silica gel (hexane to hexane/ethyl acetate 80%) togive the title compound (0.99 g; 4.2 mmol).

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.32-2.45 (m, 1H), 2.67 (s, 1H), 3.50(s, 1H), 3.88 (s, 3H), 5.92 (s, 2H), 6.55 (d, 1H), 7.10 (ddd, 1H),7.28-7.37 (m, 2H), 7.94 (d, 1H).

Preparation of Intermediate 1.3:5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenol

A solution of boron tribromide in DCM (1M; 11.7 mL; 11.7 mmol; AldrichChemical Company Inc.) [CAS-RN: 10294-33-4] was added dropwise to astirred solution of 5-fluoro-4-(4-fluoro-3-methoxyphenyl)pyridin-2-amine(988 mg; 4.18 mmol) in DCM (19 mL) at 0° C. The mixture was slowlywarmed to room temperature while stirring overnight. The mixture wascautiously diluted with a saturated, aqueous solution of sodiumbicarbonate under stirring at 0° C. and was stirred at room temperaturefor 1 hour. A saturated solution of sodium chloride was added and themixture was extracted with ethyl acetate. The combined organic layerswere filtered using a Whatman filter and concentrated to give the titlecompound (1240 mg) that was used without further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=5.92 (s, 2H), 6.48 (d, 1H), 6.96(ddd, 1H), 7.13 (dt, 1H), 7.25 (dd, 1H), 7.92 (d, 1H), 10.19 (br s, 1H).

Preparation of Intermediate 1.4: (2,6-Dichloropyridin-4-yl)methanol

To a stirred solution 2,6-dichloroisonicotinic acid (10.0 g, 52.1 mmol)[CAS-RN: 5398-44-7] in THF (300 mL) at 0° C. was added a solution ofsulfanediyldimethane-borane (1:1) [CAS-RN: 13292-87-0](16.0 g, 210.5mmol) in THF. The mixture was allowed to react at room temperatureovernight. Then MeOH (22 mL) was cautiously added to the stirred mixturewhile cooling with an ice bath. The reaction mixture was diluted withethyl acetate (300 mL), washed with an aqueous sodium hydroxide solution(1N, 100 mL) and saturated aqueous sodium chloride solution. The organiclayer was concentrated and the residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=7:1 to 3:1) to givethe title compound (8.3 g; 46.6 mmol).

¹H-NMR (400 MHz, CDCl3, 300K): δ [ppm]=2.24 (br s, 1H), 4.77 (s, 2H),7.25 (s, 2H),

Preparation of Intermediate 1.5: (2,6-dichloropyridin-4-yl)methylmethanesulfonate

(2,6-Dichloropyridin-4-yl)methanol (1.0 g; 5.62 mmol) was dissolved inDCM (20 mL) and triethyl amine (1.0 g; 9.88 mmol) was added. Theresulting mixture was cooled to 0° C. and methanesulfonyl chloride[CAS-RN: 124-63-0] (0.9 g, 7.9 mmol) was added. The mixture was stirredat room temperature for 1 hour. By adding an aqueous hydrogen chloridesolution (1N), the pH value of the mixture was adjusted to 3, before itwas extracted three times with ethyl acetate. The combined organiclayers were concentrated to give the crude title compound (1.4 g) thatwas used without further purification.

Preparation of Intermediate 1.6:2,6-Dichloro-4-[(methylsulfanyl)methyl]pyridine

(2,6-Dichloropyridin-4-yl)methyl methanesulfonate (1.40 g) was dissolvedin THF (20 mL) and a mixture of sodium thiomethoxide and sodiumhydroxide (wt 1/1, 0.70 g, 5 mmol, supplied by Shanghai DEMO MedicalTech Co., Ltd) was added. The resulting mixture was stirred overnight atroom temperature. The reaction mixture was diluted with water (10 mL)and extracted three times with ethyl acetate. The combined organiclayers were concentrated and the residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=6:1 to 3:1) to givethe title compound (0.54 g; 2.60 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.97 (s, 3H), 3.53-3.92 (s, 2H), 7.54(s, 2H).

Preparation of Intermediate 1.7:4-({6-Chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)butan-1-ol)

Sodium hydride (55-60%; 1.15 g) was added to a stirred solution ofbutane-1,4-diol (5.41 g; 60.1 mmol) in THF (165 mL) at 0° C. The icebath was removed and the reaction mixture was stirred at roomtemperature for 30 min. 2,6-dichloro-4-[(methylsulfanyl)methyl]pyridine(5.0 g; 24.0 mmol) was added and the reaction mixture was stirred underreflux overnight. After cooling the batch was concentrated and ethylacetate and water was added. The mixture was three times extracted withethyl acetate. The combined organic layers were washed with an aqueoussolution of sodium chloride, filtered using a Whatman filter andconcentrated. The residue was purified by column chromatography onsilica gel (hexane to hexane/ethyl acetate 60%) to give the titlecompound (4.3 g; 16.4 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.49-1.61 (m, 2H), 1.64-1.90 (m, 2H),1.95-2.00 (m, 3H), 3.37-3.47 (m, 2H), 3.58-3.70 (m, 2H), 4.21 (t, 2H),4.46 (t, 1H), 6.74 (s, 1H), 7.02 (d, 1H).

Preparation of Intermediate 1.8:(rac)-4-({6-chloro-4-[(methylsulfinyl)methyl]pyridin-2-yl}oxy)butan-1-ol

Iron(III)chloride (37 mg; 0.22 mmol) was added to a mixture of4-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)butan-1-ol (2000mg; 7.64 mmol) in acetonitrile (18.5 mL) and the batch was stirred atroom temperature for 10 minutes. The batch was cooled to 0° C. andperiodic acid (1.86 g; 8.18 mmol) was added under stirring in oneportion. After 5 hours the ice bath was removed and the mixture wasstirred at room temperature. Additional periodic acid (0.52 g; 2.29mmol) was added and the mixture was stirred for 2 hours at roomtemperature before it was added to a stirred solution of sodiumthiosulfate pentahydrate [CAS-RN: 10102-17-7] (10.62 g; 42.79 mmol) inice water (220 mL). The batch was stirred at room temperature for 1 hourand then extracted twice with ethyl acetate. The combined organic layerswere washed with an aqueous solution of sodium chloride, filtered usinga Whatman filter and concentrated. The residue was purified by columnchromatography on silica gel (ethyl acetate to ethyl acetate/ethanol30%) to give the title compound (1.30 g; 4.68 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.48-1.58 (m, 2H), 1.65-1.81 (m, 2H),3.35-3.51 (m, 2H), 3.90-4.05 (m, 1H), 4.13-4.26 (m, 3H), 4.45 (t, 1H),6.75 (d, 1H), 7.02 (d, 1H).

Preparation of Intermediate 1.9: (rac)-tert-butyl[{[2-chloro-6-(4-hydroxybutoxy)pyridin-4-yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate

To a suspension of(rac)-4-({6-chloro-4-[(methylsulfinyl)methyl]pyridin-2-yl}oxy)butan-1-ol(1.30 g, 4.68 mmol), tert-butyl carbamate (822 mg, 7.02 mmol), magnesiumoxide (754 mg, 18.72 mmol) and rhodium(II) acetate dimer [CAS-RN:15956-28-2] (103 mg, 0.23 mmol) in DCM (45 mL) was added iodobenzenediacetate [CAS-RN: 3240-34-4] (2.26 g, 7.02 mmol) at room temperature.The batch was stirred for 18 h at room temperature, filtered over celiteand concentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate) to give the title compound (960 mg, 2.44mmol).

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.29-1.41 (m, 9H), 1.48-1.58 (m, 2H),1.66-1.81 (m, 2H), 3.15-3.29 (m, 3H), 3.36-3.47 (m, 2H), 4.20-4.29 (m,2H), 4.46 (t, 1H), 4.91 (d, 2H), 6.86 (s, 1H), 7.08 (d, 1H).

Preparation of Intermediate 1.10:(rac)-4-[(4-{[N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl]methyl}-6-chloropyridin-2-yl)oxy]butylmethanesulfonate

Methanesulfonyl chloride [CAS-RN: 124-63-0] (133 mg; 1.16 mmol) wasadded dropwise to a stirred solution of (rac)-tert-butyl[{[2-chloro-6-(4-hydroxybutoxy)pyridin-4-yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate(380 mg; 0.97 mmol) and trimethylamine (196 mg; 1.93 mmol) in DCM (4.2mL) at 0° C. The ice bath was removed after 30 minutes and the reactionmixture was stirred for 2 hours at room temperature. The reactionmixture was diluted with water and extracted twice with ethyl acetate.The combined organic layers were filtered using a Whatman filter andconcentrated. The residue was purified by column chromatography onsilica gel (hexane to hexane/ethyl acetate 70%) to give the titlecompound (450 mg, 0.96 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.39 (s, 9H), 1.75-1.86 (m, 4H), 3.18(s, 6H), 4.22-4.31 (m, 4H), 4.91 (d, 2H), 6.88 (d, 1H), 7.10 (d, 1H).

Preparation of Intermediate 1.11: (rac)-tert-butyl{[(2-{4-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]butoxy}-6-chloropyridin-4-yl)methyl](methyl)oxido-λ⁶-sulfanylidene}carbamate

A mixture of 5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenol (seeIntermediate 1.3; 94 mg, 0.43 mmol),(rac)-4-[(4-{[N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl]methyl}-6-chloropyridin-2-yl)oxy]butylmethanesulfonate (200 mg; 0.43 mmol) potassium carbonate (70 mg; 0.51mmol) and potassium iodide (7 mg; 0.04 mmol) in DMF (3.3 mL) was stirredat 40° C. overnight. After cooling the mixture was diluted with ethylacetate and washed with water. The organic phase was concentrated andthe residue was purified by preparative HPLC (see method Autopurifier:acidic conditions) to give the title compound (70 mg; 0.12 mmol).

Example 1 Preparation of End Product

To a solution of (rac)-tert-butyl{[(2-{4-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]butoxy}-6-chloropyridin-4-yl)methyl](methyl)oxido-λ⁶-sulfanylidene}carbamate(70 mg, 0.12 mmol) in toluene (8.4 mL) and NMP (0.6 mL) was sequentiallyadded potassium phosphate (124 mg, 0.59 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [CAS-RN:564483-18-7] (5.6 mg, 0.01 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct [CAS-RN: 1028206-56-5] (9.7 mg, 0.01mmol). The suspension was degassed and heated under an atmosphere ofargon to 110° C. for 4 hours. After cooling, the reaction mixture wasdiluted with aqueous sodium chloride solution and extracted three timeswith ethyl acetate. The combined organic layers were filtered using aWhatman filter and concentrated. The residue was purified withpreparative HPLC (see method Autopurifier: acidic conditions) to givethe title compound (3 mg) still showing minor impurities.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.28-1.43 (m, 9H), 1.65-1.82 (m, 4H),3.20 (s, 3H), 4.41-4.56 (m, 4H), 4.71-4.82 (m, 2H), 6.32 (d, 1H), 6.66(s, 1H), 7.30-7.42 (m, 2H), 7.60 (d, 1H), 8.32 (d, 1H), 8.80 (d, 1H),10.02 (s, 1H).

Example 2(rac)-3,20-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene

To a solution of (rac)-tert-butyl[{[3,20-difluoro-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate(5 mg) in dichloromethane (0.2 mL) was added trifluoroacetic acid (22μL) and the mixture was stirred for 2 h. The pH value of the reactionmixture was adjusted to pH>7 by the addition of saturated aqueous sodiumbicarbonate solution. The mixture was extracted three times withdichloromethane. The combined organic layers were filtered using aWhatman filter and concentrated to give the title compound (3 mg, 6.5μmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.62-1.85 (m, 4H), 2.92 (s, 3H), 4.03(q, 1H), 4.30-4.56 (m, 7H), 6.36 (s, 1H), 6.66 (s, 1H), 7.32-7.41 (m,2H), 7.62 (d, 1H), 8.33 (d, 1H), 8.83 (d, 1H), 9.97 (s, 1H).

Example 3 (rac)-tert-butyl[{[3,20-difluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate

Preparation of Intermediate 3.1:5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenol

A batch with 2,4-dichloro-5-fluoropyrimidine [CAS-RN: 1293994-86-1](1000 mg; 5.99 mmol), (4-fluoro-3-hydroxyphenyl)boronic acid [CAS-RN:913835-74-2] (1027 mg; 6.59 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [CAS-RN:72287-26-4] (489 mg; 0.60 mmol) in 1,2-dimethoxyethane (18 mL) and 2 Maqueous solution of potassium carbonate (9 mL) was degassed using argon.The batch was stirred under an atmosphere of argon for 3 hours at 90° C.After cooling, the batch was diluted with ethyl acetate and washed withan aqueous solution of sodium chloride. The organic layer was filteredusing a Whatman filter and concentrated. The residue was purified bycolumn chromatography (hexane to hexane/ethyl acetate 30%) to give thetitle compound (307 mg; 1.3 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.33-7.41 (m, 1H), 7.53 (dddt, 1H),7.73 (dd, 1H), 8.93 (d, 1H), 10.42 (br s, 1H).

Preparation of Intermediate 3.2: 3-(Chloromethyl)-5-nitrophenol

Thionyl chloride (84.0 g; 712 mmol) was added dropwise to a stirredsolution of 3-(hydroxymethyl)-5-nitrophenol (60.0 g; 355 mmol) [CAS-RN:180628-74-4] purchased from Struchem in DMF (1200 mL) at 0° C. Themixture was stirred at 10° C. for 3 hours. The mixture was concentrated,diluted with water and extracted three times with ethyl acetate. Thecombined organic layers were washed twice with water and concentrated toafford the crude title compound (60.0 g) that was used without furtherpurification.

Preparation of Intermediate 3.3:3-[(Methylsulfanyl)methyl]-5-nitrophenol

To a solution of crude 3-(chloromethyl)-5-nitrophenol (60.0 g) inacetone (600 mL) at room temperature was added an aqueous solution ofsodium thiomethoxide (21%, 180 mL). The mixture was stirred at roomtemperature for 3 hours before additional aqueous solution of sodiumthiomethoxide (21%, 180 mL) was added and the mixture was stirred atroom temperature overnight. Finally, additional aqueous solution ofsodium thiomethoxide (21%, 90 mL) was added and the mixture was stirredat room temperature for 6 hours. The batch was diluted with ethylacetate and an aqueous solution of sodium chloride and extracted threetimes with ethyl acetate. The combined organic layers were concentratedand the residue was purified by column chromatography on silica gel(pentane/ethyl acetate 4:1) to afford the desired product (60.0 g, 302mmol).

¹H NMR (300 MHz, CDCl₃, 300K) 6=7.71 (1H), 7.57 (1H), 7.15 (1H), 3.66(2H), 1.99 (3H).

Preparation of Intermediate 3.4: ethyl4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butanoate

To a suspension of 3-[(methylsulfanyl)methyl]-5-nitrophenol (6.00 g) andpotassium carbonate (4.99 g) in DMF (58 ml) at 0° C. was added dropwiseethyl 4-bromobutanoate [CAS-RN: 2969-81-5] (4.7 mL). The mixture wasallowed to warm to room temperature and stirred for 24 h. The reactionwas diluted with water (300 mL) and the mixture was extracted threetimes with ethyl acetate (200 mL each). The combined organic layers werewashed with saturated aqueous sodium chloride, dried and concentrated toyield the title compound (11.69 g, 90% purity) that was contaminated byDMF and excess ethyl 4-bromobutanoate and which was used without furtherpurification.

¹H NMR (400 MHz, DMSO-d₆, 295 K) δ/ppm=1.15-1.21 (m, 3H), 1.94-2.03 (m,5H), 3.74-3.81 (m, 2H), 4.02-4.14 (m, 4H), 7.33-7.36 (m, 1H), 7.57-7.61(m, 1H), 7.75-7.80 (m, 1H) (one methylene group is overlayed by residualDMSO).

Preparation of Intermediate 3.5: (rac)-ethyl4-(3-{[S-methylsulfinyl]methyl}-5-nitrophenoxy)butanoate

To a solution of crude ethyl4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butanoate (11.7 g) inacetonitrile (410 mL) at 0° C. was added iron trichloride (605 mg) andthe mixture was stirred for 15 min. Then, periodic acid (25.5 g) wasadded and the reaction was stirred for 1.5 h at 0° C. The reaction wasstopped by the addition of saturated aqueous sodium thiosulfatesolution, and the mixture was extracted three times with ethyl acetate(300 mL each). The combined organic layers were washed with saturatedaqueous sodium chloride, dried and concentrated to yield the titlecompound (10.5 g, 99% purity) that was used without furtherpurification.

¹H NMR (400 MHz, DMSO-d₆, 295 K) δ/ppm=1.15-1.21 (m, 3H), 1.97-2.06 (m,2H), 4.04-4.15 (m, 5H), 4.24-4.31 (m, 1H), 7.28-7.36 (m, 1H), 7.65-7.69(m, 1H), 7.76-7.82 (m, 1H).

Preparation of Intermediate 3.6: (rac)-ethyl4-(3-{[N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl]methyl}-5-nitrophenoxy)butanoate

To a suspension of (rac)-ethyl4-(3-{[S-methylsulfinyl]methyl}-5-nitrophenoxy)butanoate (10.5 g),tert-butyl carbamate (5.60 g), magnesium oxide (5.14 g), andrhodium(II)acetate dimer [CAS-RN: 15956-28-2] (352 mg) indichloromethane (530 mL) was added iodobenzene diacetate [CAS-RN:3240-34-4] (15.4 g), and the mixture was stirred for 4.5 h at 45° C.Additional portions of tert-butyl carbamate (1.87 g), rhodium(II)acetatedimer (117 mg) and iodobenzene diacetate (5.1 g) were added, and themixture was stirred for further 12 h at 45° C. The mixture was allowedto cool to room temperature, filtered over a pad of Celite andconcentrated. The crude product was purified by flash columnchromatography (silica gel, hexanes/ethyl acetate) to yield the titlecompound (12.8 g, 97% purity).

¹H NMR (400 MHz, DMSO-d₆, 295 K) δ/ppm=1.15-1.24 (m, 3H), 1.39 (s, 9H),1.98-2.06 (m, 2H), 2.44-2.44 (m, 1H), 3.09-3.19 (m, 3H), 4.04-4.16 (m,4H), 4.95-5.10 (m, 2H), 7.41-7.47 (m, 1H), 7.73-7.80 (m, 1H), 7.88-7.94(m, 1H).

Preparation of Intermediate 3.7: (rac)-tert-butyl{[3-(4-hydroxybutoxy)-5-nitrobenzyl](methyl)oxido-P6-sulfanylidene}carbamate

To a solution of (rac)-ethyl4-(3-{[N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl]methyl}-5-nitrophenoxy)butanoate(12.8 g) in THF (210 mL) at −20° C. was added dropwisediisobutylaluminum hydride (120 mL, 1.0 M in THF). The mixture wasallowed to warm to room temperature and stirred for 2.5 h. The reactionwas stopped by the addition of saturated aqueous sodium potassiumtartrate solution. The mixture was vigorously stirred for 2 h andsubsequently extracted three times with ethyl acetate (100 mL each). Thecombined organic layers were washed with saturated aqueous sodiumchloride solution, dried and concentrated. The crude product waspurified by flash column chromatography (silica gel, hexane/ethylacetate 40%->ethyl acetate→ethyl acetate/methanol 20%) to yield thetitle compound (8.01 g, 97% purity).

¹H NMR (400 MHz, DMSO-d₆, 295 K) δ/ppm=1.39 (s, 9H), 1.51-1.65 (m, 2H),1.73-1.83 (m, 2H), 3.14 (s, 3H), 3.43-3.51 (m, 2H), 4.09-4.16 (m, 2H),4.46-4.51 (m, 1H), 4.93-5.07 (m, 2H), 7.37-7.50 (m, 1H), 7.73-7.79 (m,1H), 7.86-7.92 (m, 1H).

Preparation of Intermediate 3.8: (rac)- tert-butyl[(3-{4-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]butoxy}-5-nitrobenzyl)(methyl)oxido-λ⁶-sulfanylidene]carbamate

Under argon, diisopropyl azodicarboxylate [CAS-RN: 2446-83-5] (0.45 mL;2.27 mmol) was added dropwise to a stirred mixture of5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenol (see Intermediate3.1; 300 mg; 1.24 mmol), (rac)-tert-butyl{[3-(4-hydroxybutoxy)-5-nitrobenzyl](methyl)oxido-λ⁶-sulfanylidene}carbamate(452 mg; 1.12 mmol) and triphenylphosphine (613 mg; 2.34 mmol) in THF(29 mL) at 0° C. The ice bath was removed and the mixture was stirred atroom temperature overnight. The mixture was concentrated and the residuewas purified by column chromatography on silica gel (hexane tohexane/ethyl acetate 50%) to give the desired title compound (285 mg),still containing some impurities.

Preparation of Intermediate 3.9: (rac)-tert-butyl[(3-amino-5-{4-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]butoxy}benzyl)(methyl)oxido-λ⁶-sulfanylidene]carbamate

Platinum 1% and vanadium 2%, on activated carbon (50-70% wetted powder,44 mg) was added to a solution of (rac)-tert-butyl[(3-{4-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]butoxy}-5-nitrobenzyl)(methyl)oxido-λ⁶-sulfanylidene]carbamate(282 mg) in methanol (7 mL) and THF (2 mL) and the mixture was stirredfor 3 h at room temperature at room temperature under a hydrogenatmosphere. Additional platinum 1% and vanadium 2%, on activated carbon(50-70% wetted powder, 44 mg) was added and the mixture was stirred foradditional 3 h at room temperature under a hydrogen atmosphere. Themixture was filtered and the filtrate was concentrated to give the titlecompound that was used without further purification (231 mg).

Example 3—Preparation of the End Product

To a solution of (rac)-tert-butyl[(3-amino-5-{4-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]butoxy}benzyl)(methyl)oxido-λ⁶-sulfanylidene]carbamate(229 mg) in toluene (29 mL) and NMP (1 mL) was sequentially addedpotassium phosphate (407 mg, 1.91 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [CAS-RN:564483-18-7] (18 mg, 0.038 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct [CAS-RN: 1028206-56-5] (32 mg, 0.038mmol). The suspension was degassed and heated under argon to 110° C. for3 hours. After cooling, the reaction mixture was diluted with aqueoussodium chloride solution and extracted three times with ethyl acetate.

The combined organic layers were filtered using a Whatman filter andconcentrated. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate 30% to ethyl acetate) to give the titlecompound (53 mg; 0.09 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.38 (s, 9H), 1.66-1.88 (m, 2H),1.92-2.03 (m, 2H), 3.16 (s, 3H), 4.16 (t, 2H), 4.30 (t, 2H), 4.70-4.85(m, 2H), 6.78 (s, 1H), 6.87 (s, 1H), 7.39 (dd, 1H), 7.62-7.71 (m, 1H),8.01 (t, 1H), 8.18 (dd, 1H), 8.66 (d, 1H), 9.93 (s, 1H).

Example 4(rac)-3,20-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene

To a solution of (rac)-tert-butyl[{[3,20-difluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate(see Example 3; 53 mg; 0.09 mmol) in dichloromethane (0.7 mL) was addedtrifluoroacetic acid (0.2 mL) and the mixture was stirred for 2 h. ThepH value of the reaction mixture was adjusted to pH>7 by the addition ofsaturated aqueous sodium bicarbonate solution. The mixture was extractedthree times with ethyl acetate/THF. The combined organic layers werefiltered using a Whatman filter and concentrated. The residue waspurified by column chromatography on silica gel (DCM to DCM/ethanol 20%)to give the title compound (20 mg, 0.04 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.70-1.87 (m, 2H), 1.87-2.04 (m, 2H),2.84 (s, 3H), 3.63 (s, 1H), 4.12-4.21 (m, 2H), 4.25-4.34 (m, 4H), 6.79(s, 1H), 6.84 (s, 1H), 7.39 (dd, 1H), 7.60-7.72 (m, 1H), 7.95 (t, 1H),8.19 (dd, 1H), 8.65 (d, 1H), 9.87 (s, 1H).

Example 5 (rac)-tert-butyl[{[3,21-difluoro-13,19-dioxa-5,7,26-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaen-10-yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate

Preparation of Intermediate 5.1: methyl5-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentanoate

To a suspension of 3-[(methylsulfanyl)methyl]-5-nitrophenol (seeIntermediate 3.3; 2.00 g; 10.0 mmol) and potassium carbonate (2.08 g;15.1 mmol) in DMF (20 ml) at 0° C. was added methyl 5-bromopentanoate[CAS-RN: 5454-83-1] (1.7 mL; 12.0 mmol). The mixture was allowed to warmto room temperature and stirred overnight. The reaction was diluted withaqueous sodium chloride solution and was three times extracted withethyl acetate. The combined organic layers were filtered using a Whatmanfilter and concentrated to give the title compound (2.90 g) which wasused without further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.56-1.84 (m, 4H), 1.96 (s, 3H), 2.40(tr, 3H), 3.33 (s, 3H), 3.79 (s, 2H), 4.10 (t, 2H), 7.35 (s, 1H), 7.59(t, 1H), 7.78 (s, 1H).

Preparation of Intermediate 5.2:5-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentan-1-ol

To a solution of methyl5-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentanoate (2.90 g) in THF(45 mL) at −78° C. was added dropwise a solution of diisobutylaluminumhydride in THF (1.0 M; 32.9 mL, 32.9 mmol). The mixture was allowed towarm to 0° C. and stirred for 2 h at this temperature. Water wascautiously added and the pH was adjusted to pH 4 by the addition of anaqueous solution of hydrogen chloride (1N). The mixture was three timesextracted with ethyl acetate. The combined organic layers were washedwith saturated aqueous sodium chloride solution, filtered using aWhatman filter and concentrated. The residue was purified by flashcolumn chromatography on silica gel (hexane to hexane/ethyl acetate 70%)to give the title compound (2.40 g, 8.4 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.35-1.52 (m, 4H), 1.69-1.80 (m, 2H),1.96 (s, 3H), 3.32-3.43 (m, 2H), 3.76 (s, 3H), 3.97-4.11 (m, 2H), 4.39(t, 1H), 7.35 (s, 1H), 7.58 (t, 1H), 7.77 (t, 1H).

Preparation of Intermediate 5.3:(rac)-5-{3-[(methylsulfinyl)methyl]-5-nitrophenoxy}pentan-1-ol

To a solution of5-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}pentan-1-ol (2.30 g; 8.06mmol) in acetonitrile (215 mL) at 0° C. was added iron trichloride (38mg; 0.23 mmol) and the mixture was stirred for 15 min at roomtemperature. Periodic acid (1.97 g; 8.62 mmol) was added and thereaction was stirred for 4 h at 0° C. The ice bath was removed and thereaction was warmed to room temperature under stirring before it wasadded to a stirred solution of sodium thiosulfate pentahydrate (11.20 g;45.14 mmol) in ice water (250 mL). The batch was saturated with solidsodium chloride and extracted twice with THF and extracted twice withethyl acetate. The combined organic layers were filtered using a Whatmanfilter and concentrated. The residue was purified by flash columnchromatography on silica gel (hexane to hexane/ethyl acetate 70%) togive the title compound (1.43 g, 4.75 mmol).

1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.40-1.52 (m, 4H), 1.75 (quin,2H), 3.38-3.44 (m, 2H), 4.03-4.12 (m, 3H), 4.28 (d, 1H), 4.39 (t, 1H),7.35 (s, 1H), 7.68 (t, 1H), 7.79 (s, 1H).

Preparation of Intermediate 5.4: (rac)-tert-butyl[{3-[(5-hydroxypentyl)oxy]-5-nitrobenzyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate

To a suspension of(rac)-5-{3-[(methylsulfinyl)methyl]-5-nitrophenoxy}pentan-1-ol (1430 mg;4.75 mmol), tert-butyl carbamate (833 mg; 7.11 mmol), magnesium oxide(765 mg; 18.98 mmol), and rhodium(II)acetate dimer [CAS-RN: 15956-28-2](105 mg; 0.24 mmol) in dichloromethane (46 mL) was added iodobenzenediacetate [CAS-RN: 3240-34-4] (2293 mg; 7.12 mmol), and the mixture wasstirred at room temperature overnight. Additional portions of tert-butylcarbamate (416 mg; 3.56 mmol), magnesium oxide (382 mg; 9.49 mmol),rhodium(II)acetate dimer (52 mg; 0.12 mmol) and iodobenzene diacetate(1146 mg; 3.56 mmol) were added, and the mixture was stirred for further12 h at room temperature. The mixture was filtered over a pad of Celiteand concentrated. The residue was purified by flash columnchromatography on silica gel, (hexane to hexane/ethyl acetate 30%) togive the title compound (920 mg; 2.20 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.32-1.55 (m, 13H), 1.70-1.83 (m,2H), 3.14 (s, 3H), 3.35-3.44 (m, 2H), 4.06-4.13 (m, 2H), 4.39 (t, 1H),4.95-5.05 (m, 2H), 7.44 (s, 1H), 7.72-7.77 (m, 1H), 7.90 (s, 1H).

Preparation of Intermediate 5.5: (rac)-tert-butyl{[3-({5-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]pentyl}oxy)-5-nitrobenzyl](methyl)oxido-λ⁶-sulfanylidene}carbamate

Under an atmosphere of argon, diisopropyl azodicarboxylate [CAS-RN:2446-83-5] (0.88 mL; 4.46 mmol) was added dropwise to a stirred mixtureof 5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenol (see Intermediate3.1; 589 mg; 2.43 mmol), (rac)-tert-butyl[{3-[(5-hydroxypentyl)oxy]-5-nitrobenzyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate(920 mg; 2.21 mmol) and triphenylphosphine (1205 mg; 4.60 mmol) in THF(10 mL) at 0° C. The ice bath was removed and the mixture was stirred atroom temperature overnight. Additional portions of triphenylphosphine(1205 mg; 4.60 mmol) and diisopropyl azodicarboxylate (0.88 mL; 4.46mmol) were added and the mixture was stirred for 5 h at roomtemperature. The mixture was concentrated and the residue was purifiedby column chromatography on silica gel (hexane to hexane/ethyl acetate50%) to give the desired title compound (456 mg), still containing someimpurities.

Preparation of Intermediate 5.6: (rac)- tert-butyl{[3-amino-5-({5-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]pentyl}oxy)benzyl](methyl)oxido-λ⁶-sulfanylidene}carbamate

Platinum 1% and vanadium 2%, on activated carbon (50-70% wetted powder,117 mg) was added to a solution of (rac)-tert-butyl{[3-({5-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]pentyl}oxy)-5-nitrobenzyl](methyl)oxido-λ⁶-sulfanylidene}carbamate (456 mg; 0.71 mmol) in methanol (115 mL) andthe mixture was stirred for 2 h at room temperature under a hydrogenatmosphere. The mixture was filtered and the filtrate was concentratedto give the title compound that was used without further purification(385 mg).

Example 5—Preparation of the End Product

To a solution of (rac)- tert-butyl{[3-amino-5-({5-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]pentyl}oxy)benzyl](methyl)oxido-λ⁶-sulfanylidene}carbamate(385 mg) in toluene (47 mL) and NMP (6 mL) was sequentially addedpotassium phosphate (668 mg, 3.15 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [CAS-RN:564483-18-7] (30 mg, 0.063 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct [CAS-RN: 1028206-56-5] (52 mg, 0.063mmol). The suspension was degassed and heated under argon to 110° C. for5 hours. After cooling, the reaction mixture was diluted with aqueoussodium chloride solution and extracted twice with DCM and extractedtwice with ethyl acetate. The combined organic layers were filteredusing a Whatman filter and concentrated. The residue was purified withpreparative HPLC see method: Autopurifier: acidic conditions) to givethe title compound (60 mg; 0.10 mmol).

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.39 (s, 9H), 1.61-1.70 (m, 2H),1.81-1.87 (m, 2H), 1.88-1.97 (m, 2H), 3.16 (s, 3H), 3.97 (t, 2H),4.26-4.32 (m, 2H), 4.72-4.80 (m, 2H), 6.62 (s, 1H), 6.88 (s, 1H), 7.41(dd, 1H), 7.59-7.75 (m, 1H), 8.16 (dd, 1H), 8.47 (t, 1H), 8.68 (d, 1H),10.01 (s, 1H).

Example 6(rac)-3,21-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,7,26-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene

To a solution of (rac)-tert-butyl[{[3,21-difluoro-13,19-dioxa-5,7,26-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaen-10-yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate(58 mg; 0.10 mmol) in dichloromethane (0.90 mL) was addedtrifluoroacetic acid (0.25 mL) and the mixture was stirred for 2 h. ThepH value of the reaction mixture was adjusted to pH>7 by the addition ofsaturated aqueous sodium bicarbonate solution. The mixture was extractedthree times with ethyl acetate. The combined organic layers filteredusing a Whatman filter and concentrated. The residue was purified bypreparative HPLC (see method: Autopurifier: basic conditions) to givethe title compound (5 mg, 0.01 mmol).

¹H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.60-1.70 (m, 2H), 1.80-1.99 (m,4H), 2.85 (s, 3H), 3.62 (s, 1H), 3.97 (t, 2H), 4.23-4.34 (m, 4H), 6.63(s, 1H), 6.84 (s, 1H), 7.41 (dd, 1H), 7.56-7.75 (m, 1H), 8.16 (dd, 1H),8.42 (t, 1H), 8.67 (d, 1H), 9.95 (s, 1H).

Example 7 (rac)-tert-butyl[methyl(oxido){[3,20,23-trifluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}-1λ⁶-sulfanylidene]carbamate

Preparation of Intermediate 7.1:2-chloro-4-(2,4-difluoro-3-methoxyphenyl)-5-fluoropyrimidine

A batch with 2,4-dichloro-5-fluoropyrimidine [CAS-RN: 2927-71-1] (3978mg; 23.82 mmol), (2,4-difluoro-3-methoxyphenyl)boronic acid [CAS-RN:406482-18-6) (4925 mg; 26.21 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [CAS-RN:72287-26-4] (1945 mg; 2.38 mmol) in 1,2-dimethoxyethane (70 mL) and 2 Maqueous solution of potassium carbonate (36 mL) was degassed usingargon. The batch was stirred under an atmosphere of argon for 3 hours at100° C. After cooling, the batch was diluted with ethyl acetate andwashed with a saturated aqueous solution of sodium chloride. The organiclayer was filtered using a Whatman filter and concentrated. The residuewas purified by column chromatography (hexane to hexane/ethyl acetate33%) to give the title compound (4030 mg; 14.7 mmol).

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.99 (s, 3H), 7.39-7.43 (m, 1H), 7.45(d, 1H), 9.06 (d, 1H).

Preparation of Intermediate 7.2:3-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorophenol

A solution of boron tribromide [CAS-RN: 10294-33-4] in DCM (1M; 74.9 mL;74.9 mmol) was added dropwise to a stirred solution of2-chloro-4-(2,4-difluoro-3-methoxyphenyl)-5-fluoropyrimidine (3700 mg;13.5 mmol) in DCM (325 mL) at 0° C. The mixture was slowly warmed toroom temperature while stirring overnight. The mixture was cautiouslydiluted with a saturated, aqueous solution of sodium bicarbonate understirring at 0° C. and then solid sodium bicarbonate was added. Themixture was stirred at room temperature for 1 hour before being filteredusing a Whatman filter. The filtrate was concentrated to give the crudeproduct (2160 mg) that was used without further purification.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.15 (ddd, 1H), 7.25-7.31 (m, 1H),9.03 (d, 1H), 10.73 (br s, 1H).

Preparation of Intermediate 7.3: (rac)-tert-butyl[(3-{4-[3-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorophenoxy]butoxy}-5-nitrobenzyl)(methyl)oxido-λ⁶-sulfanylidene]carbamate

Under an atmosphere of argon, diisopropyl azodicarboxylate [CAS-RN:2446-83-5] (0.21 mL; 1.06 mmol) was added dropwise to a stirred mixtureof crude 3-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorophenol (150mg), (rac)-tert-butyl{[3-(4-hydroxybutoxy)-5-nitrobenzyl](methyl)oxido-λ⁶-sulfanylidene}carbamate(see Intermediate 3.7; 211 mg; 0.52 mmol) and triphenylphosphine (285mg; 1.09 mmol) in THF (2.5 mL) at 0° C. The ice bath was removed and themixture was stirred at room temperature for 3 days. The mixture wasconcentrated and the residue was purified by column chromatography onsilica gel (hexane to hexane/ethyl acetate 50%) to give the desiredtitle compound (309 mg), still containing some impurities.

Preparation of Intermediate 7.4: (rac)- tert-butyl[(3-amino-5-{4-[3-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorophenoxy]butoxy}benzyl)(methyl)oxido-λ⁶-sulfanylidene]carbamate

Platinum 1% and vanadium 2%, on activated carbon (50-70% wetted powder,46 mg) was added to a solution of (rac)-tert-butyl[(3-{4-[3-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorophenoxy]butoxy}-5-nitrobenzyl)(methyl)oxido-λ⁶-sulfanylidene]carbamate(307 mg) in methanol (7 mL) and THF (2 mL) and the mixture was stirredfor 3 h at room temperature under a hydrogen atmosphere. The mixture wasfiltered and the filtrate was concentrated to give the title compoundthat was used without further purification (310 mg).

Example 7—Preparation of the End Product

To a solution of (rac)-tert-butyl[(3-amino-5-{4-[3-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-difluorophenoxy]butoxy}benzyl)(methyl)oxido-λ⁶-sulfanylidene]carbamate (100 mg) in toluene (12 mL) and NMP (1.5 mL)was sequentially added potassium phosphate (172 mg, 0.81 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [CAS-RN:564483-18-7] (8 mg, 0.016 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct [CAS-RN: 1028206-56-5] (13 mg, 0.016mmol). The suspension was degassed and heated under an atmosphere ofargon to 110° C. for 3 hours. After cooling, the reaction mixture wasdiluted with aqueous sodium chloride solution and extracted three timeswith ethyl acetate. The combined organic layers were filtered using aWhatman filter and concentrated. The residue was purified withpreparative HPLC (see method: Autopurifier: acidic conditions) to givethe title compound (3 mg; 0.01 mmol).

1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.38 (s, 9H), 1.63-1.79 (m, 2H),1.80-1.95 (m, 2H), 3.13 (s, 3H), 3.90-4.01 (m, 2H), 4.37 (br t, 2H),4.64-4.78 (m, 2H), 6.57 (s, 1H), 6.84 (s, 1H), 7.32 (t, 1H), 7.47 (q,1H), 8.36 (s, 1H), 8.77 (d, 1H), 10.06 (s, 1H).

Example 8(rac)-3,20,23-trifluoro-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene

To a solution of (rac)-tert-butyl[methyl(oxido){[3,20,23-trifluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}-λ⁶-sulfanylidene]carbamate(3.0 mg; 0.005 mmol) in dichloromethane (0.5 mL) was addedtrifluoroacetic acid (0.012 mL) and the mixture was stirred for 2 h. ThepH value of the reaction mixture was adjusted to pH>7 by the addition ofsaturated aqueous sodium bicarbonate solution. The mixture was extractedwith three times with ethyl acetate. The combined organic layers werefiltered using a Whatman filter and concentrated to give the titlecompound (2.6 mg, 0.005 mmol).

¹H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.62-1.78 (m, 2H), 1.80-1.99 (m,2H), 2.99 (s, 3H), 3.87-4.05 (m, 2H), 4.33-4.49 (m, 4H), 6.59 (s, 1H),6.83 (s, 1H), 7.32 (t, 1H), 7.41-7.65 (m, 1H), 8.35 (t, 1H), 8.77 (d,1H), 10.05 (s, 1H).

Example 9 (rac)-tert-butyl[{[3,19-difluoro-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1^(2,6)1^(8,12)]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaen-10-yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate

Preparation of Intermediate 9.1:3-{3-[(Methylsulfanyl)methyl]-5-nitrophenoxy}propan-1-ol

3-Bromopropan-1-ol (1.13 g; 8.1 mmol) was added dropwise to a stirredmixture of 3-[(methylsulfanyl)methyl]-5-nitrophenol (see Intermediate3.3; 1.5 g; 7.5 mmol) and potassium carbonate (1.25 g; 9.0 mmol) in DMF(15 mL) at 0° C. The ice bath was removed and the reaction mixture wasstirred overnight at room temperature. The reaction mixture was dilutedwith an aqueous solution of sodium chloride and extracted three timeswith ethyl acetate. The combined organic layers were filtered using aWhatman filter and concentrated. The residue was purified by columnchromatography on silica gel (hexane to hexane/ethyl acetate 60%) togive the title compound (1.6 g; 6.2 mmol).

¹H NMR (400 MHz, DMSO, 300K) δ=1.85-1.97 (m, 5H), 3.56 (q, 2H), 3.80 (s,2H), 4.15 (t, 2H), 4.60 (t, 1H), 7.36 (s, 1H), 7.58 (t, 1H), 7.78 (s,1H).

Preparation of Intermediate 9.2:(rac)-3-{3-[(methylsulfinyl)methyl]-5-nitrophenoxy}propan-1-ol

(rac)-3-{3-[(methylsulfinyl)methyl]-5-nitrophenoxy}propan-1-ol (1.30 g;4.8 mmol) was prepared from3-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}propan-1-ol (1.30 g; 5.1mmol) under similar conditions as described in the preparation protocolfor Intermediate 5.3.

¹H NMR (400 MHz, DMSO, 300K) δ=1.89 (quin, 2H), 3.36-3.59 (m, 2H),4.00-4.10 (m, 1H), 4.12-4.19 (m, 2H), 4.28 (d, 1H), 4.61 (t, 1H), 7.35(dd, 1H), 7.69 (t, 1H), 7.79 (s, 1H).

Preparation of Intermediate 9.3: (rac)-tert-butyl{[3-(3-hydroxypropoxy)-5-nitrobenzyl](methyl)oxido-λ⁶-sulfanylidene}carbamate

(rac)-tert-butyl{[3-(3-hydroxypropoxy)-5-nitrobenzyl](methyl)oxido-λ⁶-sulfanylidene}carbamate(1.10 g; 2.8 mmol) was prepared from(rac)-3-{3-[(methylsulfinyl)methyl]-5-nitrophenoxy}propan-1-ol (1.30 g;4.8 mmol) under similar conditions as described in the preparationprotocol for Intermediate 5.4.

¹H NMR (400 MHz, DMSO, 300K) δ=1.39 (s, 9H), 1.89 (quin, 2H), 3.14 (s,3H), 3.54-3.59 (m, 2H), 4.17 (t, 2H), 4.61 (t, 1H), 4.96-5.05 (m, 2H),7.45 (dd, 1H), 7.76 (t, 1H), 7.90 (t, 1H).

Preparation of Intermediate 9.4: (rac)-tert-butyl[(3-{3-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]propoxy}-5-nitrobenzyl)(methyl)oxido-λ⁶-sulfanylidene]carbamate

(rac)-tert-butyl[(3-{3-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]propoxy}-5-nitrobenzyl)(methyl)oxido-λ⁶-sulfanylidene]carbamate(293 mg; 0.48 mmol) was prepared from5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenol (206 mg; 0.85 mmol)and (rac)-tert-butyl{[3-(3-hydroxypropoxy)-5-nitrobenzyl](methyl)oxido-λ⁶-sulfanylidene}carbamate(300 mg; 0.77 mmol) under similar conditions as described in thepreparation protocol for Intermediate 5.5.

¹H NMR (400 MHz, DMSO, 300K) δ=1.36 (s, 9H), 2.26-2.32 (m, 2H), 3.14 (s,3H), 4.28-4.36 (m, 4H), 4.95-5.05 (m, 2H), 7.44-7.50 (m, 2H), 7.61-7.68(m, 1H), 7.76-7.81 (m, 2H), 7.91 (t, 1H), 8.98 (d, 1H).

Preparation of Intermediate 9.5: (rac)-tert-butyl[(3-amino-5-{3-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]propoxy}benzyl)(methyl)oxido-λ⁶-sulfanylidene]carbamate

(rac)-tert-butyl[(3-amino-5-{3-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]propoxy}benzyl)(methyl)oxido-λ⁶-sulfanylidene]carbamate(148 mg) was prepared as a crude product from (rac)-tert-butyl[(3-{3-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]propoxy}-5-nitrobenzyl)(methyl)oxido-λ6-sulfanylidene]carbamate(293 mg; 0.48 mmol) under similar conditions as described in thepreparation protocol for Intermediate 5.6.

Example 9—Preparation of the End Product

(rac)-tert-butyl[{[3,19-difluoro-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1^(2,6).1^(8,12)]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaen-10-yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate(31 mg; 0.06 mmol) was prepared from crude (rac)-tert-butyl[(3-amino-5-{3-[5-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorophenoxy]propoxy}benzyl)(methyl)oxido-λ⁶-sulfanylidene]carbamate(148 mg; 0.25 mmol) under similar conditions as described in thepreparation protocol for Example 5. The product was purified bypreparative HPLC (see method: Autopurifier: basic conditions).

¹H-NMR (400 MHz, DMSO-d6)=1.37 (s, 9H), 2.14-2.31 (m, 2H), 3.13 (s, 3H),4.32 (br t, 2H), 4.47 (br t, 2H), 4.74 (s, 2H), 6.70 (s, 1H), 6.84 (s,1H), 7.36 (dd, 1H), 7.46-7.58 (m, 1H), 8.09-8.16 (m, 2H), 8.67 (d, 1H),9.91 (s, 1H).

Example 10

(rac)-3,19-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1^(2,6).1^(8,12)]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaene

(rac)-3,19-difluoro-10-[(S-methylsulfonimidoyl)methyl]-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1^(2,6).1^(8,12)]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaene(9 mg; 0.02 mmol) was prepared from (rac)-tert-butyl[{[3,19-difluoro-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1^(2,6).1^(8,12)]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaen-10-yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate(28 mg; 0.05 mmol) under similar conditions as described in thepreparation protocol for Example 6.

¹H-NMR (400 MHz, DMSO-d6)=2.16-2.31 (m, 2H), 2.81 (s, 3H), 4.15-4.34 (m,4H), 4.43-4.62 (m, 2H), 6.71 (s, 1H), 6.82 (s, 1H), 7.32-7.41 (m, 1H),7.47-7.62 (m, 1H), 8.05-8.15 (m, 2H), 8.66 (d, 1H), 9.85 (s, 1H).

Example 11

(rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene

Preparation of Intermediate 11.1:5-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]pentan-2-one

A mixture of 5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenol(Intermediate 1.3; 1.00 g; 4.50 mmol), 5-chloropentan-2-one (1.63 g;13.5 mmol), potassium carbonate (1.86 g; 13.5 mmol) and potassium iodide(0.07 g; 0.45 mmol) in DMF (20 mL) was stirred for 4 h at 80° C.Additional chloropentan-2-one (0.81 g; 6.75 mmol) and potassiumcarbonate (0.62 g; 4.50 mmol) was added and the mixture was stirred at80° C. overnight. After cooling the mixture was diluted with water andthe mixture was three times extracted with ethyl acetate. The combinedorganic layers were filtered using a Whatman filter and concentrated.The residue was purified by column chromatography on silica gel (DCM toDCM/EtOH 20%) to give the title compound (1.20 g; 3.91 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.77-1.99 (m, 2H), 2.11 (s, 3H), 2.61(t, 2H), 4.07 (t, 2H), 5.92 (s, 2H), 6.53 (d, 1H), 7.10 (ddd, 1H), 7.28(d, 1H), 7.33 (t, 1H), 7.94 (d, 1H).

Preparation of Intermediate 11.2:(rac)-5-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]pentan-2-ol

Sodium borohydride (0.30 g; 7.84 mmol) was added portionwise to astirred solution of5-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]pentan-2-one (1.20g; 3.91 mmol) in methanol (18 mL) at 0° C. After the addition the icebath was removed and the mixture was stirred at room temperature for 1h. The mixture was concentrated using a rotovab. The residue was takenup with ethyl acetate and was washed two times with a saturated aqueoussolution of sodium bicarbonate. The organic phase was filtered using aWhatman filter and concentrated. The residue was purified by columnchromatography on silica gel (hexane to hexane/ethylacetate 100%) togive the title compound (0.70 g; 2.27 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.07 (d, 3H), 1.40-1.53 (m, 2H),1.62-1.89 (m, 2H), 3.60-3.69 (m, 1H), 4.09 (t, 2H), 4.45 (d, 1H), 5.92(s, 2H), 6.54 (d, 1H), 7.09 (ddt, 1H), 7.28 (d, 1H), 7.30-7.36 (m, 1H),7.94 (d, 1H).

Preparation of Intermediate 11.3:6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-ol

Potassium hydroxide (2.0 g; 36.0 mmol) was added to a solution of2,6-dichloro-4-[(methylsulfanyl)methyl]pyridine (Intermediate 1.6; 5.0g; 24.0 mmol) in tert-butanol (150 mL) and the mixture was stirred at100° C. overnight. After cooling the mixture was diluted with asaturated aqueous solution of sodium chloride and extracted three timeswith ethyl acetate. The combined organic layers were filtered using aWhatman filter and concentrated. The residue was taken up in ethylacetate and washed with aqueous hydrogen chloride solution. The organiclayer was filtered using a Whatman filter and concentrated. The residuewas stirred in hexane for 1 h before it was filtered and dried in vacuoto give the title compound (2.3 g; 12.1 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.96 (s, 3H), 3.62 (s, 2H), 6.54 (s,1H), 6.88 (s, 1H), 11.48 (br s, 1H).

Preparation of Intermediate 11.4:(rac)-4-(3-{[4-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)pentyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine

Under argon, diisopropyl azodicarboxylate [CAS-RN: 2446-83-5] (0.98 mL;5.00 mmol) was added dropwise to a stirred mixture of (rac)5-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]pentan-2-ol(Intermediate 11.2; 1.40 g; 4.54 mmol),6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-ol (Intermediate 11.3; 861mg; 4.54 mmol) and triphenylphosphine (1.31 g; 5.00 mmol) in DCM (28 mL)and the mixture was stirred at room temperature overnight. The mixturewas concentrated and the residue was purified by column chromatographyon silica gel (hexane to hexane/ethyl acetate 80%) to give the desiredtitle compound (1.50 g; 3.13 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.29 (d, 3H), 1.73-1.90 (m, 4H), 1.95(s, 3H), 3.62 (s, 2H), 4.09-4.16 (m, 2H), 5.09-5.17 (m, 1H), 5.92 (s,2H), 6.53 (d, 1H), 6.68 (s, 1H), 6.99 (d, 1H), 7.09 (ddd, 1H), 7.25-7.35(m, 2H), 7.93 (d, 1H).

Example 11: Preparation of End Product

To a solution of(rac)-4-(3-{[4-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)pentyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine(1.50 g, 3.13 mmol) in toluene (225 mL) and NMP (15 mL) was sequentiallyadded potassium phosphate (3.32 g, 15.63 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl [CAS-RN:564483-18-7] (149 mg, 0.31 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct [CAS-RN: 1028206-56-5] (258mg, 0.31 mmol). The suspension was degassed and stirred under anatmosphere of argon at 110° C. overnight. After cooling, the reactionmixture was diluted with an aqueous, saturated sodium chloride solutionand extracted three times with ethyl acetate. The combined organiclayers were filtered using a Whatman filter and concentrated. Theresidue was purified by column chromatography on silica gel (hexane tohexane/ethyl acetate 40%) to give the desired title compound (1.30 g;2.93 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.11 (d, 3H), 1.37-1.60 (m, 2H),1.81-2.04 (m, 5H), 3.50-3.62 (m, 2H), 4.36-4.48 (m, 2H), 5.19-5.27 (m,1H), 6.20 (s, 1H), 6.60 (s, 1H), 7.37 (d, 2H), 7.58 (d, 1H), 8.30 (d,1H), 8.68 (d, 1H), 9.83 (s, 1H).

Example 12 and 13 Enantiomers of3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene

(rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene(1.30 g; Example 11) was separated into the single enantiomers bypreparative chiral HPLC.

System: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario4000 Column: YMC Amylose SA, 5 μm 250 × 30 mm Solvent: Hexane/EtOH 1:1Flow: 40 mL/min Temperature: 25° C. Solution: 1.30 g in 6 ml DCM/MeOH1:1 Injection: 6 × 1 mL Detection: UV 280 nm Retention time in minpurity in % yield Example 12 5.9-8.1 98.1% 150 mg Enantiomer 1 Example13 10.1-12.4 94.2% 126 mg Enantiomer 2

Examples 14 and 15 Diastereoisomers 1 and 2 of3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene

Ammonium carbamate (38 mg; 0.49 mmol) and (diacetoxyiodo)benzene (221mg; 0.69 mmol) were added to a solution of3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene(Enantiomer 1, example 12; 145 mg; 0.33 mmol) in methanol (2.2 mL). Themixture was stirred in an open flask for 2 hours at room temperaturebefore it was concentrated. The residue was purified with preparativeHPLC (see method: Autopurifier: acidic conditions) to give the mixtureof two diastereoisomers (32 mg; 0.06 mmol). The mixture of twodiastereoisomers was then separated into the single diastereoisomers bypreparative chiral HPLC.

System: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario4000 Column: YMC Amylose SA, 5 μm 250 × 30 mm Solvent: tert-Butyl methylether/MeOH 1:1 Flow: 40 mL/min Temperature: 25° C. Solution: 20 mg in 1mL DCM/MeOH 1:1 Injection: 1 × 1 mL Detection: UV 280 nm Retention timein min purity in % yield Example 14 5.4-6.1 99.2% 4.5 mg Diasteroisomer1 Example 15 6.9-8.1 99.5% 3.6 mg Diasteroisomer 2

Example 14: 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.09-1.17 (m, 3H),1.43 (br dd, 1H), 1.57 (td, 1H), 1.82-2.04 (m, 2H), 2.86 (s, 3H),3.72-3.79 (m, 1H), 4.24-4.48 (m, 4H), 5.21-5.29 (m, 1H), 6.33 (s, 1H),6.67 (s, 1H), 7.34-7.40 (m, 2H), 7.59 (d, 1H), 8.31 (d, 1H), 8.67 (d,1H), 9.92 (s, 1H).

Example 15: 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.08-1.17 (m, 3H),1.35-1.48 (m, 1H), 1.48-1.66 (m, 1H), 1.86 (ddt, 1H), 1.94-2.03 (m, 1H),2.87 (s, 3H), 3.71-3.79 (m, 1H), 4.25-4.34 (m, 2H), 4.36-4.49 (m, 2H),5.21-5.29 (m, 1H), 6.32 (s, 1H), 6.67 (s, 1H), 7.34-7.40 (m, 2H), 7.59(br d, 1H), 8.31 (d, 1H), 8.67 (d, 1H), 9.91 (s, 1H).

Examples 16 and 17 Diastereoisomers 3 and 4 of3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene

Ammonium carbamate (32 mg; 0.41 mmol) and (diacetoxyiodo)benzene (186mg; 0.58 mmol) were added to a solution of3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene(Enantiomer 2, example 12; 122 mg; 0.28 mmol) in methanol (1.9 mL). Themixture was stirred in an open flask for 2 hours at room temperaturebefore it was concentrated. The residue was purified with preparativeHPLC (see method: Autopurifier: acidic conditions) to give the mixtureof two diastereoisomers (32 mg; 0.06 mmol). The mixture of twodiastereoisomers was separated into the single diastereoisomers bypreparative chiral HPLC.

System: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario4000 Column: YMC Amylose SA, 5 μm 250 × 30 mm Solvent: tert-Butyl methylether/MeOH 1:1 Flow: 40 mL/min Temperature: 25° C. Solution: 20 mg in 1mL DCM/MeOH 1:1 Injection: 1 × 1 mL Detection: UV 280 nm Retention timein min purity in % yield Example 16 14.1-16.2 99.7% 9.0 mgDiasteroisomer 3 Example 17 16.9-18.9 97.0% 8.3 mg Diasteroisomer 4

Example 16: 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.09-1.17 (m, 3H),1.43 (br s, 1H), 1.57 (br d, 1H), 1.87 (br d, 1H), 1.94-2.03 (m, 1H),2.87 (s, 3H), 3.75 (s, 1H), 4.29 (d, 2H), 4.38-4.48 (m, 2H), 5.25 (br d,1H), 6.32 (s, 1H), 6.67 (s, 1H), 7.38 (d, 2H), 7.60 (d, 1H), 8.32 (d,1H), 8.67 (d, 1H), 9.92 (s, 1H).

Example 17: 1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.06-1.18 (m, 3H),1.44 (br d, 1H), 1.57 (br d, 1H), 1.82-1.93 (m, 1H), 1.99 (br s, 1H),2.86 (s, 3H), 3.75 (s, 1H), 4.24-4.35 (m, 2H), 4.38-4.48 (m, 2H),5.21-5.31 (m, 1H), 6.33 (s, 1H), 6.67 (s, 1H), 7.38 (d, 2H), 7.60 (d,1H), 8.32 (d, 1H), 8.68 (d, 1H), 9.92 (s, 1H).

Example 18(rac)-3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene

Preparation of Intermediate 18.1: (rac)-5-hydroxyhexyl methanesulfonate

Methanesulfonyl chloride (2.6 mL; 33.8 mmol) was added dropwise to astirred solution of hexane-1,5-diol (5.1 mL; 42.3 mmol) andtriethylamine (5.9 mL; 42.3 mmol) in DCM (182 mL) at 0° C. The mixturewas stirred at 0° C. for 30 min before the ice bath was removed and themixture was stirred for 3 hours at room temperature. The mixture wasdiluted with an aqueous solution of sodium chloride and extracted twotimes with DCM. The combined organic layers were filtered using aWhatman filter and concentrated. The residue was taken up in ethylacetate and the solution was washed with water and two times withaqueous sodium chloride solution. The organic layer was filtered using aWhatman filter and concentrated to give the crude product (5.6 g), thatwas used without further purification.

Preparation of Intermediate 18.2: 6365-26-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]hexan-2-ol

(rac)-5-Hydroxyhexyl methanesulfonate (697 mg; 3.56 mmol) was slowlyadded to a mixture of 5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenol(Intermediate 1.3; 790 mg; 3.56 mmol), potassium carbonate (589 mg; 4.27mmol) and potassium iodide (59 mg; 0.36 mmol) in DMF (28 mL) at 0° C.The mixture was stirred at 60° C. overnight. After cooling, the mixturewas diluted with ethyl acetate and washed with aqueous sodium chloridesolution. The organic layer was filtered using a Whatman filter andconcentrated. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate 50% to ethyl acetate 100%) to give thedesired title compound (688 mg, 2.13 mmol).

1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.00-1.06 (m, 3H), 1.26-1.54 (m,4H), 1.68-1.79 (m, 2H), 3.53-3.63 (m, 1H), 4.00-4.11 (m, 2H), 4.36 (d,1H), 5.92 (s, 2H), 6.54 (d, 1H), 7.09 (ddt, 1H), 7.26-7.35 (m, 2H),7.92-7.96 (m, 1H).

Preparation of Intermediate 18.3:(rac)-4-(3-{[5-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)hexyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine

(rac)-4-(3-{[5-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)hexyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine(530 mg; 1.07 mmol) was prepared from6-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]hexan-2-ol (685 mg;2.13 mmol) and 6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-ol(Intermediate 11.3; 403 mg; 2.13 mmol) under similar conditions asdescribed in the preparation protocol for Intermediate 11.4.

1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.15-1.29 (m, 3H), 1.41-1.81 (m,6H), 1.95 (s, 3H), 3.63 (s, 2H), 4.00-4.14 (m, 2H), 5.08 (sxt, 1H), 5.91(s, 2H), 6.53 (d, 1H), 6.68 (d, 1H), 6.98 (d, 1H), 7.08 (ddt, 1H),7.25-7.34 (m, 2H), 7.93 (d, 1H).

Example 18: Preparation of End Product

(rac)-3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene(215 mg; 0.47 mmol) was prepared from(rac)-4-(3-{[5-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)hexyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine(528 mg; 1.07 mmol) under similar conditions as described in thepreparation protocol for Example 11.

1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.11 (d, 3H), 1.39-1.54 (m, 1H),1.57-1.82 (m, 4H), 1.90-2.00 (m, 4H), 3.52-3.60 (m, 2H), 4.36 (br t,2H), 5.11-5.19 (m, 1H), 6.19 (s, 1H), 6.55 (s, 1H), 7.24-7.45 (m, 3H),8.25 (d, 1H), 8.31 (d, 1H), 9.77 (s, 1H).

Example 19 and 20 Enantiomers of3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene

(rac)-3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene(1.32 g) was separated into the single enantiomers by preparative chiralHPLC.

System: Sepiatec: Prep SFC100 Column: Chiralpak IG, 5 μm 250 × 30 mmSolvent: CO₂/EtOH; 40% EtOH Flow: 100 mL/min Temperature: 40° C.Solution: 1.32 g in 17.5 ml DCM/MeOH/DMSO 1:1:1.5 Injection: 20 × 0.9 mLDetection: UV 254 nm Retention time in min purity in % yield Example 196.5-8.5 97.1% 560 mg Enantiomer 1 Example 20  9.8-12.8 98.8% 385 mgEnantiomer 2

Example 21 Mixture of Two Diastereoisomers 1 and 2 of3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene

The mixture of diastereoisomers 1 and 2 of3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene(12 mg; 0.02 mmol) was prepared from enantiomer 1 of3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene(Example 19; 505 mg; 1.10 mmol) under similar conditions as described inthe preparation protocol for Examples 14 and 15.

1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.09-1.16 (m, 3H), 1.36-1.55 (m,1H), 1.58-1.82 (m, 4H), 1.86-2.06 (m, 1H), 2.86 (d, 3H), 3.71-3.88 (m,1H), 4.20-4.40 (m, 4H), 4.99-5.31 (m, 1H), 6.12-6.45 (m, 1H), 6.50-6.71(m, 1H), 7.18-7.49 (m, 3H), 8.14-8.28 (m, 1H), 8.28-8.44 (m, 1H),9.76-9.99 (m, 1H).

Example 22 Mixture of Two Diastereoisomers 3 and 4 of3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene

The mixture of diastereoisomers 3 and 4 of3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene(27 mg; 0.06 mmol) was prepared from enantiomer 2 of3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene(Example 20; 330 mg; 0.72 mmol) under similar conditions as described inthe preparation protocol for Examples 14 and 15.

1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.10-1.14 (m, 3H), 1.49 (br d,1H), 1.59-1.82 (m, 4H), 1.89-2.00 (m, 1H), 2.87 (d, 3H), 3.76 (s, 1H),4.23-4.39 (m, 4H), 5.12-5.20 (m, 1H), 6.32 (dd, 1H), 6.61 (d, 1H), 7.28(br s, 1H), 7.33-7.45 (m, 2H), 8.24 (dd, 1H), 8.32 (d, 1H), 9.84 (d,1H).

Example 23(rac)-3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene

Preparation of Intermediate 23.1: (rac)-6-hydroxyheptyl methanesulfonate

Crude (rac)-6-hydroxyheptyl methanesulfonate (4.0 g) was prepared fromheptane-1,6-diol (3.5 g; 26.5 mmol) under similar conditions asdescribed in the preparation protocol for Intermediate 18.1.

Preparation of Intermediate 23.2:(rac)-7-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]heptan-2-ol

(rac)-7-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]heptan-2-ol(528 mg; 1.57 mmol) was prepared from crude (rac)-6-hydroxyheptylmethanesulfonate (748 mg) and5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenol (Intermediate 1.3; 790mg; 3.56 mmol) under similar conditions as described in the preparationprotocol for Intermediate 18.2.

1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.03 (d, 3H), 1.23-1.45 (m, 6H),1.69-1.79 (m, 2H), 3.57 (dt, 1H), 4.09 (t, 2H), 4.32 (d, 1H), 5.92 (s,2H), 6.54 (d, 1H), 7.06-7.12 (m, 1H), 7.26-7.36 (m, 2H), 7.92-7.96 (m,1H).

Preparation of Intermediate 23.3:(rac)-4-(3-{[6-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)heptyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine

(rac)-4-(3-{[6-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)heptyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine(573 mg; 1.13 mmol) was prepared from(rac)-7-[5-(2-amino-5-fluoropyridin-4-yl)-2-fluorophenoxy]heptan-2-ol(476 mg; 1.42 mmol)) and 6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-ol(Intermediate 11.3; 268 mg; 1.42 mmol) under similar conditions asdescribed in the preparation protocol for Intermediate 18.3.

Example 23: Preparation of End Product

(rac)-3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene(224 mg; 0.48 mmol) was prepared from(rac)-4-(3-{[6-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)heptyl]oxy}-4-fluorophenyl)-5-fluoropyridin-2-amine(571 mg; 1.12 mmol) under similar conditions as described in thepreparation protocol for Example 18.

1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.05 (d, 3H), 1.29-1.55 (m, 5H),1.62-1.75 (m, 3H), 1.99-2.02 (m, 3H), 3.53-3.60 (m, 2H), 4.28 (dt, 1H),4.36-4.45 (m, 1H), 4.82-4.90 (m, 1H), 6.16-6.19 (m, 1H), 6.57 (s, 1H),7.25-7.39 (m, 2H), 7.50 (dd, 1H), 8.29 (d, 1H), 8.53 (d, 1H), 9.81 (s,1H).

Example 24 and 25 Enantiomers of3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene

(rac)-3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene(150 mg) was separated into the single enantiomers by preparative chiralHPLC.

System: Sepiatec: Prep SFC100 Column: Chiralpak IA, 5 μm 250 × 30 mmSolvent: CO₂/EtOH; 35% EtOH Flow: 100 mL/min Temperature: 40° C.Solution: 150 mg in 2 mL DMSO Injection: 5 × 0.4 mL Detection: UV 254 nmRetention time in min purity in % yield Example 24 5.5-7.0 99.7% 65 mgEnantiomer 1 Example 25  7.4-10.0 97.6% 75 mg Enantiomer 2

Example 26 Mixture of Two Diastereoisomers 1 and 2 of3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene

The mixture of diastereoisomers 1 and 2 of3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene(14 mg; 0.03 mmol) was prepared from Enantiomer 1 of3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene(Example 24; 60 mg; 0.13 mmol) under similar conditions as described inthe preparation protocol for Examples 14 and 15.

1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.02-1.10 (m, 3H), 1.30-1.60 (m,5H), 1.61-1.78 (m, 3H), 2.88 (s, 3H), 3.76 (s, 1H), 4.25-4.33 (m, 3H),4.40 (s, 1H), 4.79-4.95 (m, 1H), 6.30 (s, 1H), 6.64 (s, 1H), 7.29 (br s,1H), 7.34-7.40 (m, 1H), 7.50 (d, 1H), 8.30 (d, 1H), 8.53 (dd, 1H), 9.89(d, 1H).

Example 27 Mixture of Two Diastereoisomers 3 and 4 of3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene

The mixture of diastereoisomers 3 and 4 of3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene(6 mg; 0.01 mmol) was prepared from Enantiomer 2 of3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene(Example 25; 70 mg; 0.15 mmol) under similar conditions as described inthe preparation protocol for Examples 14 and 15.

1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.04-1.14 (m, 3H), 1.30-1.56 (m,5H), 1.58-1.79 (m, 3H), 2.88 (s, 3H), 3.76 (s, 1H), 4.24-4.44 (m, 4H),4.86 (br s, 1H), 6.30 (s, 1H), 6.64 (s, 1H), 7.25-7.43 (m, 2H), 7.50(dd, 1H), 8.24-8.32 (m, 1H), 8.53 (dd, 1H), 9.83-9.91 (m, 1H).

Example 28 Mixture of enantiomers of3,20-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene

3-Chloroperbenzoic acid (23 mg; 0.14 mmol) was added to a solution of(rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene(30 mg; 0.07 mmol) in DCM (0.7 mL) at 0° C. The ice bath was removed andthe mixture was stirred at room temperature for 1 hour. The mixture wasdiluted with an aqueous solution of sodium bicarbonate and extracted twotimes with DCM. The combined organic layers were filtered using aWhatman filter and concentrated. The residue was purified withpreparative HPLC (see method: Autopurifier: acidic conditions) to givethe title compound (7 mg; 0.01 mmol).

1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.11 (d, 3H), 1.40 (br dd, 1H),1.53-1.62 (m, 1H), 1.81-1.94 (m, 1H), 1.97-2.01 (m, 1H), 2.94-3.00 (m,3H), 4.30-4.46 (m, 4H), 5.19-5.27 (m, 1H), 6.28 (s, 1H), 6.65 (s, 1H),7.33-7.40 (m, 2H), 7.56 (br d, 1H), 8.30 (d, 1H), 8.65 (d, 1H), 9.90 (s,1H).

Examples 29 and 30 Enantiomer 1 and 2 of3,21-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene

3-Chloroperbenzoic acid (75 mg; 0.43 mmol) was added to a solution of(rac)-3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene(Example 18; 100 mg; 0.22 mmol) in DCM (2.1 mL) at 0° C. The ice bathwas removed and the mixture was stirred at room temperature for 1 hour.The mixture was diluted with an aqueous solution of sodium bicarbonateand extracted two times with DCM. The combined organic layers werefiltered using a Whatman filter and concentrated. The residue waspurified with preparative HPLC (see method: Autopurifier: acidicconditions) to give the racemate (32 mg; 0.07 mmol).

1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.12 (d, 3H), 1.49 (br d, 1H),1.58-1.83 (m, 4H), 1.87-2.01 (m, 1H), 2.99 (s, 3H), 4.32-4.47 (m, 4H),5.12-5.21 (m, 1H), 6.28 (s, 1H), 6.62 (s, 1H), 7.27 (br dd, 1H), 7.36(t, 1H), 7.43 (d, 1H), 8.24 (d, 1H), 8.33 (d, 1H), 9.90 (s, 1H).

The racemate was separated into the single enantiomers by preparativechiral HPLC.

System: Sepiatec: Prep SFC100 Column: Chiralpak IA, 5 μm 250 × 30 mmSolvent: CO₂/EtOH + 0.2 vol % aqueous ammonia (32%); 50% EtOH Flow: 100mL/min Temperature: 40° C. Solution: 150 mg in 2 mL DMSO Injection: 5 ×0.4 mL Detection: UV 220 nm Retention time in min purity in % yieldExample 29 7.1-9.1 99.7% 5 mg Enantiomer 1 Example 30 10.1-13.1 97.9% 5mg Enantiomer 2

Example 31 and 32 Enantiomer 1 and 2 of3,22-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]hexacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene

3-Chloroperbenzoic acid (71 mg; 0.31 mmol) was added to a solution of(rac)-3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene (Example 23; 68 mg;0.14 mmol) in DCM (3.5 mL) at 0° C. The ice bath was removed and themixture was stirred at room temperature for 3 hours. The mixture wasdiluted with an aqueous solution of sodium bicarbonate and extracted twotimes with DCM. The combined organic layers were filtered using aWhatman filter and concentrated. The residue was purified withpreparative HPLC (see method: Autopurifier: acidic conditions) to givethe racemate (35 mg; 0.07 mmol).

1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=1.06 (d, 3H), 1.32-1.56 (m, 5H),1.64-1.74 (m, 3H), 3.00 (s, 3H), 4.27 (dt, 1H), 4.39-4.46 (m, 3H),4.83-4.91 (m, 1H), 6.26 (d, 1H), 6.64 (d, 1H), 7.26-7.31 (m, 1H),7.34-7.39 (m, 1H), 7.51 (dd, 1H), 8.31 (d, 1H), 8.52 (d, 1H), 9.95 (s,1H).

The racemate was separated into the single enantiomers by preparativechiral HPLC.

System: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario4000 Column: YMC Amylose SA, 5 μm 250 × 30 mm Solvent: Hexane/EtOH 60:40Flow: 40 mL/min Temperature: 25° C. Solution: 31 mg in 1 mL DCM/MeOH 1:1Injection: 1 × 1 mL Detection: UV 254 nm Retention time in min purity in% yield Example 31 14.2-16.0 98.1% 15 mg Enantiomer 1 Example 3220.0-22.0 96.6% 15 mg Enantiomer 2

The following Table 1 provides an overview on the compounds described inthe example section:

TABLE 1 Example No. Structure Name of compound 1

(rac)-tert-butyl [{[3,20-difluoro-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10- yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate 2

(rac)-3,20-difluoro-10-[(S- methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene 3

(rac)-tert-butyl [{[3,20-difluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-10- yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate 4

(rac)-3,20-difluoro-10-[(S- methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11.19,21-nonaene 5

(rac)-tert-butyl [{[3,21-difluoro-13,19-dioxa-5,7,26-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaen-10- yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate 6

(rac)-3,21-difluoro-10-[(S- methylsulfonimidoyl)methyl]-13,19-dioxa-5,7,26-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene 7

(rac)-tert-butyl [methyl(oxido){[3,20,23- trifluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(24),2(25),3,5,8(24),9,11,19,21-nonaen-10-yl]methyl}-1λ⁶-sulfanylidene]carbamate 8

(rac)-3,20,23-trifluoro-10-[(S- methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene 9

(rac)-tert-butyl [{[3,19-difluoro-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1^(2,6).1^(8,12)]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaen-10- yl]methyl}(methyl)oxido-λ⁶-sulfanylidene]carbamate 10

(rac)-3,19-difluoro-10-[(S- methylsulfonimidoyl)methyl]-13,17-dioxa-5,7,24-triazatetracyclo[16.3.1.1^(2,6).1^(8,12)]tetracosa-1(22),2(24),3,5,8(23),9,11,18,20-nonaene 11

(rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene 12

Enantiomer 1 of (rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene 13

Enantiomer 2 of (rac)-3,20-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene 14

Diastereoisomer 1 of 3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene 15

Diastereoisomer 2 of 3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene 16

Diastereoisomer 3 of 3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene 17

Diastereoisomer 4 of 3,20-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene 18

(rac)-3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene 19

Enantiomer 1 of 3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene 20

Enantiomer 2 of 3,21-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene 21

Mixture of diastereoisomers 1 and 2 of 3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]- 13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene 22

Mixture of diastereoisomers 3 and 4 of 3,21-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]- 13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene 23

(rac)-3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene 24

Enantiomer 1 of 3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene 25

Enantiomer 2 of 3,22-difluoro-14-methyl-10-[(methylsulfanyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene 26

Mixture of diastereoisomers 1 and 2 of 3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]- 13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene 27

Mixture of diastereoisomers 3 and 4 of 3,22-difluoro-14-methyl-10-[(S-methylsulfonimidoyl)methyl]- 13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene 28

Mixture of enantiomers of 3,20-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,18-dioxa-5,7,24-triazatetracyclo[17.3.1.1^(2,6).1^(8,12)]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene 29

Enantiomer 1 of 3,21-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene 30

Enantiomer 2 of 3,21-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,19-dioxa-5,7,25-triazatetracyclo[18.3.1.1^(2,6).1^(8,12)]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene 31

Enantiomer 1 of 3,22-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]hexacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene 32

Enantiomer 2 of 3,22-difluoro-14-methyl-10-[(methylsulfonyl)methyl]-13,20-dioxa-5,7,26-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]hexacosa-1(25),2(27),3,5,8(26),9,11,21,23-nonaene

Results:

Table 2: Inhibition for CDK9 and CDK2 of compounds according to thepresent invention

The IC₅₀ (inhibitory concentration at 50% of maximal effect) values areindicated in nM, “n.t.” means that the compounds have not been tested inthe respective assay.

-   {circle around (1)}: Example Number-   {circle around (2)}: high ATP CDK9: CDK9/CycT1 kinase assay as    described under Method 1b. of Materials and Methods-   {circle around (3)}: high ATP CDK2: CDK2/CycE kinase assay as    described under Method 2b. of Materials and Methods-   {circle around (4)}: Selectivity high ATP CDK9 over high ATP CDK2:    IC₅₀ (high ATP CDK2)/IC₅₀ (high ATP CDK9) according to Methods 1b.    and 2b. of Materials and Methods

Noteworthily, in the CDK9 assays, as described supra in the Methods 1a.and 1b. of Materials and Methods, resolution power is limited by theenzyme concentrations, the lower limit for IC₅₀s is about 1-2 nM in theCDK9 high ATP assay and 2-4 nM in the CDK low ATP assays. For compoundsexhibiting IC₅₀s in this range the true affinity to CDK9 and thus theselectivity for CDK9 over CDK2 might be even higher, i.e. for thesecompounds the selectivity factors calculated in columns 4 and 7 of Table2, infra, are minimal values, they could be also higher.

TABLE 2 {circle around (1)} Structure {circle around (2)} {circle around(3)} {circle around (4)} 2

7 737 105 3

5 >20000 >4000 4

3 1540 513 5

24 >20000 >833 6

5 16200 3240 8

17 6520 385 10

25 4750 190 11

7 4670 667 12

4 6450 1613 13

4 711 178 14

3 1510 503 15

3 1620 540 16

2 144 72 17

1 132 132 18

32 >20000 >625 19

138 >20000 >145 20

23 12600 548 21

2 2450 1225 22

2 501 251 23

67 >20000 >298 24

68 >20000 >294 25

93 >20000 >215 26

4 13000 3250 27

5 2720 544 28

2 360 189 29

4 691 173 30

3 3590 1196 31

16 >20000 1250 32

18 4980 277

Tables 3a and 3b: Inhibition of proliferation of HeLa, HeLa-MaTu-ADR,NCI-H460, DU145, Caco-2, B16F10, A2780 and MOLM-13 cells by compoundsaccording to the present invention, determined as described under Method3. of Materials and Methods. All IC₅₀ (inhibitory concentration at 50%of maximal effect) values are indicated in nM, “n.t.” means that thecompounds have not been tested in the respective assay.

{circle around (1)}: Example Number

{circle around (2)}: Inhibition of HeLa cell proliferation{circle around (3)}: Inhibition of HeLa-MaTu-ADR cell proliferation{circle around (4)}: Inhibition of NCI-H460 cell proliferation{circle around (5)}: Inhibition of DU145 cell proliferation{circle around (6)}: Inhibition of Caco-2 cell proliferation{circle around (7)}: Inhibition of B16F10 cell proliferation{circle around (8)}: Inhibition of A2780 cell proliferation{circle around (9)}: Inhibition of MOLM-13 cell proliferation

TABLE 3a Indications represented by cell lines Cell line SourceIndication HeLa ATCC Human cervical tumour HeLa-MaTu-ADR EPO-GmbHMultidrug-resistant human Berlin cervical carcinoma NCI-H460 ATCC Humannon-small cell lung carcinoma DU 145 ATCC Hormone-independent humanprostate carcinoma Caco-2 ATCC Human colorectal carcinoma B16F10 ATCCMouse melanoma A2780 ECACC Human ovarian carcinoma MOLM-13 DSMZ Humanacute myeloid leukemia

TABLE 3b Inhibition of proliferation {circle around (1)} Structure{circle around (2)} {circle around (3)} {circle around (4)} {circlearound (5)} {circle around (6)} {circle around (7)} {circle around (8)}{circle around (9)}  2

90 78 157 85 96 110 9 27  3

244 218 267 206 163 270 56 108  4

150 140 331 138 177 176 41 20  5

964 1000 479 585 658 993 >100 228  6

199 169 277 121 144 171 39 140  8

177 179 217 196 181 224 68 45 10

128 155 238 180 159 209 48 33 11

n.t. n.t. n.t. n.t. n.t. n.t. 346 n.t. 14

n.t. n.t. n.t. n.t. n.t. n.t. 23 n.t. 15

n.t. n.t. n.t. n.t. n.t. n.t. 16 n.t. 16

n.t. n.t. n.t. n.t. n.t. n.t. 6 n.t. 17

n.t. n.t. n.t. n.t. n.t. n.t. 6 n.t. 21

n.t. n.t. n.t. n.t. n.t. n.t. 27 n.t. 22

n.t. n.t. n.t. n.t. n.t. n.t. 0.7 n.t. 26

n.t. n.t. n.t. n.t. n.t. n.t. 53 n.t. 27

n.t. n.t. n.t. n.t. n.t. n.t. 102 n.t. 28

n.t. n.t. n.t. n.t. n.t. n.t. 16. n.t. 29

n.t. n.t. n.t. n.t. n.t. n.t. 25 n.t. 30

n.t. n.t. n.t. n.t. n.t. n.t. 55 n.t. 31

n.t. n.t. n.t. n.t. n.t. n.t. 121 n.t. 32

n.t. n.t. n.t. n.t. n.t. n.t. 146 n.t.

Table 4: Equilibrium dissociation constants K_(D) [M], dissociation rateconstants k_(off) [l/s], and target residence times [min] as determinedby Method 8.

Dissociation rate constants below of what is resolvable with therespective assay are reported using the “<”-symbol (e.g. <8.0 E-5 s⁻¹).

Values labeled with “*” represent arithmetic means of more than onevalue.

{circle around (1)}: Example Number

{circle around (2)}: Equilibrium dissociation constant K_(D) [M]{circle around (3)}: Dissociation rate constant k_(off) [l/s]{circle around (4)}: Target residence time [min]

TABLE 4 {circle around (1)} Structure {circle around (2)} {circle around(3)} {circle around (4)}  2

1.2 E−9*   2.2 E−4*  75*  4

1.2 E−9*   6.7 E−4*  25* 16

2.8 E−10  6.6 E−11  2.4 E−11  2.9 E−11  <8.0 E−5  <8.0 E−5  1.3 E−4 <8.0E−5  >208 >208  131 >208 17

7.7 E−11* <8.0 E−5* >208* 21

1.0 E−9*   1.6 E−3*  10* 22

1.9 E−10*  3.9 E−4*  43* 28

9.2 E−11  9.1 E−11  1.2 E−10  1.5 E−13  3.5 E−4 <8.0 E−5  3.1 E−4 <8.0E−5   48 >208  54 >208

It is expected that that the prolonged residence time of macrocyclicCDK9 inhibitors according to the invention will result in a sustainedinhibitory effect on CDK9 signaling, ultimately contributing tosustained target engagement and anti-tumor efficacy.

1.-27. (canceled)
 28. A compound of general formula (7):

wherein: Z is hydrogen or fluorine; L is a C₃-C₈-alkylene moiety; wherein said moiety is optionally substituted with (i) one substituent selected from hydroxy, —NR⁸R⁹, C₂-C₃-alkenyl-, C₂-C₃-alkynyl-, C₃-C₄-cycloalkyl-, hydroxy-C₁-C₃-alkyl, and —(CH₂)NR⁸R⁹, and/or (ii) one or two or three or four substituents, identically or differently, selected from halogen and C₁-C₃-alkyl-; or wherein one carbon atom of said C₃-C₈-alkylene moiety forms a three- or four-membered ring together with a bivalent moiety to which it is attached, wherein said bivalent moiety is selected from —CH₂CH₂—, —CH₂CH₂CH₂—, and —CH₂OCH₂—; R¹ is C₁-C₆-alkyl-, C₃-C₆-alkenyl-, C₃-C₇-cycloalkyl-, or heterocyclyl-; wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C₁-C₆-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₆-alkoxy-, C₁-C₃-fluoroalkoxy-, —NH₂, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, —OP(═O)(OH)₂, —C(═O)OH, and —C(═O)NH₂; R² is hydrogen, fluorine, chlorine, bromine, cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, or C₁-C₃-fluoroalkoxy-; R³ and R⁴ are independently from each other, a group selected from hydrogen, fluorine, chlorine, bromine, cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, and C₁-C₃-fluoroalkoxy-; and R⁸ and R⁹ are independently from each other, a group selected from hydrogen, C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-, and heteroaryl-; wherein said C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl-, benzyl- or heteroaryl-group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C₁-C₃-alkyl-, and C₁-C₃-fluoroalkoxy-, or R⁸ and R⁹, together with the nitrogen atom they are attached to, form a cyclic amine; or salt thereof.
 29. The compound of claim 28, wherein: Z is hydrogen or fluorine; L is a C₃-C₅-alkylene moiety, wherein said moiety is optionally substituted with i) one substituent selected from hydroxy, C₃-C₄-cycloalkyl-, and hydroxy-C₁-C₃-alkyl-, and —(CH₂)NR⁸R⁹, and/or ii) one or two or three substituents, identically or differently, selected from halogen and C₁-C₃-alkyl-; R¹ is C₁-C₆-alkyl- or C₃-C₅-cycloalkyl-; wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C₁-C₃-alkyl-, fluoro-C₁-C₂-alkyl-, C₁-C₃-alkoxy-, C₁-C₂-fluoroalkoxy-, —NH₂, alkylamino-, dialkylamino-, cyclic amines, —OP(═O)(OH)₂, —C(═O)OH, and —C(═O)NH₂; R² is hydrogen, fluorine, chlorine, cyano, C₁-C₂-alkyl-, C₁-C₂-alkoxy-, fluoro-C₁-C₂-alkyl-, or C₁-C₂-fluoroalkoxy-; R³ and R⁴ are independently from each other, a group selected from hydrogen, fluorine, chlorine, cyano, C₁-C₂-alkyl-, C₁-C₂-alkoxy-, fluoro-C₁-C₂-alkyl-, and C₁-C₂-fluoroalkoxy-; and R⁸ and R⁹ are independently from each other, a group selected from hydrogen, C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-, phenyl-, and benzyl-; wherein said C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-, phenyl- or benzyl- group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, cyclic amines, fluoro-C₁-C₂-alkyl-, and C₁-C₂-fluoroalkoxy-, or R⁸ and R⁹, together with the nitrogen atom they are attached to, form a cyclic amine; or a salt thereof.
 30. The compound of claim 28, wherein; Z is hydrogen or fluorine; L is a C₃-C₅-alkylene moiety, wherein said moiety is optionally substituted with (i) one substituent selected from C₃-C₄-cycloalkyl- and hydroxymethyl, and/or (ii) one or two or three C₁-C₂-alkyl- group substituents, identically or differently; R¹ is C₁-C₄-alkyl- or C₃-C₅-cycloalkyl-; wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C₁-C₂-alkyl-, C₁-C₂-alkoxy-, —NH₂, and —C(═O)OH; R² is hydrogen, fluorine, chlorine, cyano, methyl-, methoxy-, trifluoromethyl-, or trifluoromethoxy-; R³ is hydrogen, fluorine, chlorine, cyano, methyl-, methoxy-, trifluoromethyl-, or trifluoromethoxy-; R⁴ is hydrogen or fluorine; or a salt thereof.
 31. The compound of claim 28, wherein; Z is hydrogen or fluorine; L is C₃-C₅-alkylene; R¹ is C₁-C₄-alkyl optionally substituted with one or two substituents, identically or differently, selected from the group consisting of hydroxy, C₁-C₂-alkoxy-, —NH₂, and —C(═O)OH; R² is hydrogen or fluorine; R³ is hydrogen, fluorine, or methoxy; and R⁴ is hydrogen; or a salt thereof.
 32. The compound of claim 28, wherein; L is C₃-C₅-alkylene; or a salt thereof.
 33. The compound of claim 28, wherein; Z is hydrogen or fluorine; L is C₃-C₅-alkylene; R¹ is methyl; R² is hydrogen; R³ is hydrogen or fluorine; and R⁴ is hydrogen; or a salt thereof.
 34. The compound of claim 28, wherein: Z is hydrogen or fluorine; L is C₃-C₅-alkylene; R¹ is C₁-C₃-alkyl; R² is hydrogen or fluorine; R³ is hydrogen, fluorine, or methoxy; and R⁴ is hydrogen; or a salt thereof.
 35. The compound of claim 28, wherein: Z is hydrogen or fluorine; L is C₄-C₅-alkylene; R¹ is methyl; R² is hydrogen; R³ is hydrogen or fluorine; and R⁴ is hydrogen; or a salt thereof.
 36. The compound of claim 28, wherein; Z is hydrogen or fluorine, R³ is fluorine; and R⁴ is hydrogen; or a salt thereof.
 37. The compound of claim 28, wherein: Z is hydrogen or fluorine, L is C₃-C₅-alkylene; R¹ is methyl; R² is hydrogen; R³ is fluorine; and R⁴ is hydrogen; or a salt thereof.
 38. A compound of general formula (19):

wherein: Z is hydrogen or fluorine; L is a C₃-C₈-alkylene moiety; wherein said moiety is optionally substituted with (i) one substituent selected from hydroxy, —NR⁸R⁹, C₂-C₃-alkenyl-, C₂-C₃-alkynyl-, C₃-C₄-cycloalkyl-, hydroxy-C₁-C₃-alkyl, and —(CH₂)NR⁸R⁹, and/or (ii) one or two or three or four substituents, identically or differently, selected from halogen and C₁-C₃-alkyl-; or wherein one carbon atom of said C₃-C₈-alkylene moiety forms a three- or four-membered ring together with a bivalent moiety to which it is attached, wherein said bivalent moiety is selected from —CH₂CH₂—, —CH₂CH₂CH₂—, and —CH₂OCH₂—; R¹ is C₁-C₆-alkyl-, C₃-C₆-alkenyl-, C₃-C₇-cycloalkyl-, or heterocyclyl-; wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C₁-C₆-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₆-alkoxy-, C₁-C₃-fluoroalkoxy-, —NH₂, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, —OP(═O)(OH)₂, —C(═O)OH, and —C(═O)NH₂; R² is hydrogen, fluorine, chlorine, bromine, cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, or C₁-C₃-fluoroalkoxy-; R³ and R⁴ are independently from each other, a group selected from hydrogen, fluorine, chlorine, bromine, cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, and C₁-C₃-fluoroalkoxy-; and R⁸ and R⁹ are independently from each other, a group selected from hydrogen, C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-, and heteroaryl-; wherein said C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl-, benzyl- or heteroaryl-group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C₁-C₃-alkyl-, and C₁-C₃-fluoroalkoxy-, or R⁸ and R⁹, together with the nitrogen atom they are attached to, form a cyclic amine; or salt thereof.
 39. The compound of claim 38, wherein: Z is hydrogen or fluorine; L is a C₃-C₅-alkylene moiety, wherein said moiety is optionally substituted with i) one substituent selected from hydroxy, C₃-C₄-cycloalkyl-, and hydroxy-C₁-C₃-alkyl-, and —(CH₂)NR⁸R⁹, and/or ii) one or two or three substituents, identically or differently, selected from halogen and C₁-C₃-alkyl-; R¹ is C₁-C₆-alkyl- or C₃-C₅-cycloalkyl-; wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C₁-C₃-alkyl-, fluoro-C₁-C₂-alkyl-, C₁-C₃-alkoxy-, C₁-C₂-fluoroalkoxy-, —NH₂, alkylamino-, dialkylamino-, cyclic amines, —OP(═O)(OH)₂, —C(═O)OH, and —C(═O)NH₂; R² is hydrogen, fluorine, chlorine, cyano, C₁-C₂-alkyl-, C₁-C₂-alkoxy-, fluoro-C₁-C₂-alkyl-, or C₁-C₂-fluoroalkoxy-; R³ and R⁴ are independently from each other, a group selected from hydrogen, fluorine, chlorine, cyano, C₁-C₂-alkyl-, C₁-C₂-alkoxy-, fluoro-C₁-C₂-alkyl-, and C₁-C₂-fluoroalkoxy-; and R⁸ and R⁹ are independently from each other, a group selected from hydrogen, C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-, phenyl-, and benzyl-; wherein said C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-, phenyl- or benzyl- group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, cyclic amines, fluoro-C₁-C₂-alkyl-, and C₁-C₂-fluoroalkoxy-, or R⁸ and R⁹, together with the nitrogen atom they are attached to, form a cyclic amine; or a salt thereof.
 40. The compound of claim 38, wherein: Z is hydrogen or fluorine; L is a C₃-C₅-alkylene moiety, wherein said moiety is optionally substituted with (i) one substituent selected from C₃-C₄-cycloalkyl- and hydroxymethyl, and/or (ii) one or two or three C₁-C₂-alkyl- group substituents, identically or differently; R¹ is C₁-C₄-alkyl- or C₃-C₅-cycloalkyl-; wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C₁-C₂-alkyl-, C₁-C₂-alkoxy-, —NH₂, and —C(═O)OH; R² is hydrogen, fluorine, chlorine, cyano, methyl-, methoxy-, trifluoromethyl-, or trifluoromethoxy-; R³ is hydrogen, fluorine, chlorine, cyano, methyl-, methoxy-, trifluoromethyl-, or trifluoromethoxy-; R⁴ is hydrogen or fluorine; or a salt thereof.
 41. The compound of claim 38, wherein: Z is hydrogen or fluorine; L is C₃-C₅-alkylene; R¹ is C₁-C₄-alkyl optionally substituted with one or two substituents, identically or differently, selected from the group consisting of hydroxy, C₁-C₂-alkoxy-, —NH₂, and —C(═O)OH; R² is hydrogen or fluorine; R³ is hydrogen, fluorine, or methoxy; and R⁴ is hydrogen; or a salt thereof.
 42. The compound of claim 38, wherein: L is C₃-C₅-alkylene; or a salt thereof.
 43. The compound of claim 38, wherein: Z is hydrogen or fluorine; L is C₃-C₅-alkylene; R¹ is methyl; R² is hydrogen; R³ is hydrogen or fluorine; and R⁴ is hydrogen; or a salt thereof.
 44. The compound of claim 38, wherein: Z is hydrogen or fluorine; L is C₃-C₅-alkylene; R¹ is C₁-C₃-alkyl; R² is hydrogen or fluorine; R³ is hydrogen, fluorine, or methoxy; and R⁴ is hydrogen; or a salt thereof.
 45. The compound of claim 38, wherein: Z is hydrogen or fluorine; L is C₄-C₅-alkylene; R¹ is methyl; R² is hydrogen; R³ is hydrogen or fluorine; and R⁴ is hydrogen; or a salt thereof.
 46. The compound of claim 38, wherein: Z is hydrogen or fluorine, R³ is fluorine; and R⁴ is hydrogen; or a salt thereof.
 47. The compound of claim 38, wherein: Z is hydrogen or fluorine, L is C₃-C₅-alkylene; R¹ is methyl; R² is hydrogen; R³ is fluorine; and R⁴ is hydrogen; or a salt thereof. 